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Immune Reconstitution and Immunotherapy in HIV Infection CME

Author: Bruce D. Walker, MD

Complete author affiliations and disclosures are at the end of this activity.

Immune Reconstitution and Immunotherapy in HIV Infection

Abstract

Detailed immunologic studies have begun to define the immune responses that are associated
with a favorable outcome in the setting of HIV infection. In particular, these include virus-specific
cytotoxic T-lymphocyte responses and T-helper-cell responses; antibody responses also are
likely to contribute. These findings may provide a rational target for immunotherapy in persons
with progressive infection and have sparked an increasing effort to develop new methods to
augment immunity. In addition, the advent of highly active antiretroviral therapy has led to
evidence of partial immune reconstitution in persons with chronic infection, and the ability to
control viremia with drugs has paved the way for new options for manipulation of host immunity.
Recent new data indicating that early treatment of acute infection leads to control of viremia
after stopping therapy provide clear evidence that the immune system can gain the upper hand
against HIV and provides a strong rationale for attempts to extend these advances to persons
with chronic infection. New insights into the mechanisms of impaired effector function in HIV
infection offer new avenues to immune augmentation. However, the magnitude of the challenge
at hand is underscored by recent descriptions of HIV superinfection. An understanding of the
rationale for immunotherapy and the prospects for individual clinical trials that are planned or
underway is essential in counseling patients about these novel therapies. It is also of great
importance to understand the differences between acute and chronic HIV infection and why the
prospects for immune control are different in these 2 groups of persons. This review will
describe the immunopathogenesis of HIV infection, discuss why immunotherapy holds promise
in infected persons, and examine the status of current approaches.

Introduction

An understanding of the potential for immunotherapy and immune reconstitution in HIV infection
requires a detailed understanding of the host immune response to this virus. (For additional
information on this topic, see part 1 of this review, "Immunopathogenesis and Immune
Response in HIV Infection.") Recent studies dissecting immune responses in situations in which
transient immune control is achieved and then lost are examined in detail to provide insights into
the breadth and magnitude of immune responses that are likely to be needed for persistent
control of infection. Specific immunotherapeutic strategies that are being pursued or planned will
then be discussed, with particular attention to recent data showing that immune control of HIV
can be induced in persons already infected with the virus.

Immune Reconstitution in the Era of HAART

General Immune Function


One of the hallmarks of HIV infection is chronic immune activation, which persists for years. The
extent to which the body can maintain this state of activation has been the subject of much
debate. Early T-cell turnover studies suggested that CD4+ cells were being produced and
destroyed at a rate well over 10- to 20-fold in excess of what is normally observed,[1] although
more recent estimates put this figure at closer to 3-fold.[2,3] There has been much debate on the
causes of lymphopenia, with studies suggesting both an increased destruction of CD4+ cells as
well as a block in T-cell production, which may be alleviated by HAART. There may also be a
defect in thymic production of cells, as measured by molecular studies of recent thymic
emigrants. Indeed, poor CD4+ cell count recovery in some patients treated with HAART may be
due to failure of thymic production.[4] However, the lower levels of recent thymic emigrants
measured in the peripheral blood may simply reflect a greater peripheral expansion of cells in
the setting of chronic immune activation.[5]

The chronic immune activation in HIV infection is ultimately inadequate to eradicate the virus, or
even to hold it in relative check over the long duration of infection. This likely relates to the fact
that HIV is essentially an infection of the immune system and is associated with an inexorable
decline in immune function in untreated persons. Because infection is associated with
destruction of the thymic and lymph node architecture,[6] it has been speculated that irreversible
damage might occur relatively early in infection, such that the prospects for any meaningful
immune recovery even with potent antiviral therapies might be limited. Since the introduction of
HAART, it has been possible to measure directly the effects of viral control on the immune
system. Data have also accumulated indicating that the incidence of opportunistic infections and
malignancies is dramatically decreased.[7] These observations suggest reasons for cautious
optimism regarding the potential for immune reconstitution.

The first indication that HAART might result in some measure of immune reconstitution came
from studies of CD4+ cell number in persons whose viral load had been successfully
suppressed by antiretroviral drug therapy. Dramatic increases in CD4+ cell counts have been
documented in some persons, and these increases are associated with a decreased risk of
opportunistic infections and death.

Further evidence that HAART may lead to meaningful immune reconstitution came from more
detailed longitudinal quantitation of naive cells in persons initiating HAART. In a pivotal article
published in 1997, Autran and colleagues[8] examined key surface molecules on CD4+ cells in
advanced patients who were being treated with antiretroviral regimens for the first time.
Treatment with zidovudine, zalcitabine, and ritonavir led to a rapid reduction in viral load that
was sustained through 12 months of follow-up. During the first 2 weeks of treatment there was a
rapid rise in CD4+ cell number, which continued as a slow but persistent rise, yielding a positive
linear slope of +10%. Mean CD4+ percentage increased from 12% to 18%, remaining below the
normal 45% but nevertheless showing a substantial increase compared with baseline. This
increase was predominantly due to memory cells during the first 4 months, but was then
followed by a significant rise in naive CD4+ cells. The late rises in naive CD4+ cells were
associated with overall decreases in CD4+ cell activation markers, consistent with antiviral-
induced interruption of ongoing viral replication. Functional studies revealed an increase in T-
cell proliferative responses to recall antigens and mitogens, but no recovery of HIV-1-specific T-
cell responses. More recent studies in persons treated with protease inhibitors have shown
sustained increases in CD4+ cell count after virologic failure, suggesting that even transient
reductions in viral load may have more sustained effects on overall immunologic function.[9]
Studies in children also show that treatment with HAART is associated with repopulation of the
CD4+ cell compartment, independent of age.[10]

Other studies of HAART in HIV-infected persons have yielded largely similar results, with later
increases in naive cells observed, as well as increases in functional immune responses to recall
antigens. Although increases in HIV-1-specific immune responses have been observed in some
studies, these have been modest.[9,11-13] The HAART-induced increases in naive cells must be
seen as extremely promising, if these cells can be educated to target HIV. Other recent studies
suggest that there may also be restoration of a broader T-cell repertoire with HAART, although
this has not always been observed.[14] It is the availability of naive cell reconstitution with HAART,
the lack of recovery of HIV-1-specific immunity, and the finding that CD8+ responses may be
impaired in vivo (see above) that provide a rationale for pursuing therapeutic vaccination in
infected persons.

Other recent studies also suggest that HAART may lead to recovery of functional immune
responses to certain pathogens. Komanduri and colleagues[15] studied specific immune
responses to cytomegalovirus (CMV) in infected persons receiving HAART. They found that
end-organ disease due to CMV was highly associated with lack of CMV-specific lymphocyte
responses, and that these responses could be readily detected after treatment with ganciclovir
and HAART. Although this was a cross-sectional analysis, it does suggest that restoration of
antigen-specific immune responses can be achieved with aggressive control of viremia.

In addition, recent studies demonstrate that prophylaxis for opportunistic infections may be
discontinued based on quantitative recovery of CD4+ cells. For example, azithromycin
prophylaxis has been successfully discontinued in persons treated with HAART once the CD4+
cell count has reached 100 cells/mm3.[16]

Thymic Function

It was long considered that thymic function decreases with age and is not present or not
functional in adults. This view was based on observations in humans and animal models that
the volume of thymic tissue progressively decreases with increasing age, and naive cell
repopulation after myeloablative chemotherapy is delayed and less robust in adults vs
children.[17] In HIV infection, it has been assumed that this progressive thymic dysfunction would
be accentuated because of direct viral effects on the thymus: HIV appears to be able to infect
thymocytes as well as thymic epithelium.[18]

Studies offer reasons for optimism regarding the potential for the thymus to contribute to
immune reconstitution (reviewed by McCune[19]). In a study using computed tomography scan to
measure thymus volume and flow cytometry to determine the frequency of naive cells, McCune
and associates[20] provided the first evidence that the thymus might remain active in at least
some HIV-infected adults. Abundant thymic tissue could be detected in 47 of 99 HIV-1-
seropositive adults, aged 20-59, and was also associated with both higher CD4+ cell counts and
higher percentages of circulating naive CD4+ lymphocytes. A higher prevalence of abundant
thymic tissue in persons aged 40 years and older was observed in HIV-infected persons,
perhaps indicating that the thymus is responding to HIV-induced decreases in CD4+ cell counts
with enhanced function. Similar increases in thymic function have also been observed in
children infected with HIV who initiate HAART.[21] Recent studies suggesting that the thymus
remains active into adult life and that HAART results in increased thymic output of naive
precursors in infected persons encourage optimism that functional immunity might ultimately be
restored.[22] The ability to measure recent thymic emigrants by quantitation of T-cell receptor
excision circles (TRECs; a measure of recent emigration from the thymus) has provided
important insights. In the SIV model, experimental infection leads to reduced levels of TRECs
beginning at 16-30 weeks postinfection, and these correlate with histologic changes indicative of
dysfunction within the thymic tissue.[23] Complementing these findings are studies showing that
the gains in CD4+ cell count during HAART are associated with residual thymic function.
Persons with poor CD4+ cell count increases on HAART had significantly less thymic tissue and
lower levels of TRECs detectable in the blood.[4]

One major concern regarding immune reconstitution is that of cellular senescence.


Lymphocytes appear to have a finite ability to undergo cell division. With each subsequent
round of replication there is a subsequent decrease in telomer length, providing a means of
assessing the replicative capacity of a cell. HIV infection is associated with shortening of
telomer length in the CD8+ population, suggesting that these cells may be working overtime.[24]
This has not been observed in CD4+ cells,[25] possibly because of a shortened survival of these
cells in vivo. One recent study raises concerns about the long-term effects of an activated
immune response against HIV.[26] A 55-year-old patient with long-term nonprogressing HIV
infection who had an undetectable viral load developed progressive decline in his CD4+ cell
count, in the absence of an increase in viral load. This patient, who had been infected for more
than 15 years at the time of the CD4+ cell decline, was then started on antiviral therapy. His
CD4+ cell count has thus far been slow to rise, raising the possibility that prolonged immune
activation and increasing age, among other factors, may be associated with thymic dysfunction
and the inability to sustain such responses. It will be very important to determine the cause of
the CD4+ decline and also to determine whether HAART will result in increased CD4+ cell
counts in this person. Likewise, it will be important to monitor persons who are controlling
viremia in the absence of antiviral therapy as they get older, to see if there is evidence of
immune exhaustion.

HIV-Specific Immunity

As discussed earlier, studies indicate that HIV-1-specific immune responses, particularly cellular
immune responses, play a critical role in determining the viral set point, and may be responsible
for maintaining the virus in check in persons who are LTNPs. Thus, the ability to restore these
responses has to be considered a key factor in immune reconstitution. The majority of studies
have shown little reconstitution of HIV-specific cellular immunity with prolonged HAART, at least
when therapy is initiated during the chronic phase of infection, although there are some
exceptions.[23,24, 26-29] This is particularly true for HIV-1-specific T-helper-cell responses[8,9,11,12] and is
in contrast to the observed increases in cellular immune responses to other pathogens, such as
CMV. What can be the explanation for this observation?

One possible explanation is that HIV-1-specific T-helper-cell responses may be significantly


impaired in the earliest stages of untreated acute infection. Acute HIV infection should elicit a
strong HIV-1-specific T-helper-cell response, which would be expected to orchestrate an
effective antiviral immune response. However, HIV-1 selectively infects activated CD4+ cells,[30]
and thus these cells may become preferential targets for infection during the period when viral
load is at its highest. This has now been conclusively demonstrated through analysis of viral
burden in HIV-1-specific CD4+ cells. Douek and colleagues[31] have shown that viral DNA burden
is greater in HIV-specific CD4+ cells than in other memory cells, and that these cells are
particularly vulnerable to infection during the transition from naive to memory cells. Loss or
dysfunction of these cells would be expected to impair downstream events, including activation
of CTL (Figure 7). In addition to direct infection of HIV-1-specific CD4+ cells, it is possible that
these cells may undergo activation-induced cell death in the presence of high antigen load in
the early stages of acute infection, further diminishing their numbers.[32] This latter explanation
would fit better with the observation that T-helper-cell responses may also be lacking in persons
with progressive hepatitis C virus (HCV) infection.[33,34] Since HCV does not infect CD4+ cells, a
unifying hypothesis to account for the lack of T-helper-cell responses in both HIV and HCV
infection would be activation-induced cell death due to overstimulation of virus-specific CD4+
cells at the time of enormously high levels of viremia in the acute phase of infection.

Figure. Activated HIV-specific T-helper cells are required for activation of CTL.
If the hypothesis that virus-specific CD4+ cell responses are lost in early stages of infection is
true, then one would expect that early intervention with HAART in persons with acute HIV
infection may be associated with enhanced HIV-1-specific T-helper-cell function. This is indeed
exactly what is seen: Some persons treated with potent antiviral therapy before seroconversion
develop HIV-1-specific T-helper-cell responses to Gag analogous to those seen in persons who
are spontaneously controlling viremia in the absence of antiviral therapy.[35-38] In contrast, HAART
does not readily lead to augmentation of these responses in persons who are started on therapy
at a later stage of infection. The window of opportunity for HAART-induced augmentation of T-
helper-cell responses has not been defined. We have seen some persons who have developed
detectable responses when started on therapy even 6 months after acute infection,[39] but more
studies of persons started on therapy after seroconversion are needed to determine the
frequency with which such responses can be anticipated.

It is also important to mention that potent antiretroviral therapy instituted in the chronic phase of
infection has been associated with declines in HIV-1-specific immunity, particularly CTL
responses.[40-42] This is presumably due to the lack of ongoing antigenic stimulation needed to
maintain these responses over the chronic phase of infection. However, even though responses
decline, newer, more sensitive assays demonstrate that these cells are still present, albeit at
lower magnitude.[43] The loss of these cells may be accelerated by the lack of virus-specific T-
helper-cell responses, which may influence the antigenic threshold for maintenance of these
responses (unpublished data). Such observations suggest that therapeutic immunization may
be beneficial in persons who have complete suppression of viremia on prolonged HAART.

Case Study: Part 3

In the context of the clinical trial, a blood specimen was obtained and examined for evidence of
HIV-1-specific T-helper-cell responses to Gag and Env proteins. At the time of presentation, there
were no detectable immune responses to either protein. The patient returned to clinic weekly to
assess adherence and to further evaluate virus-specific immune responses. As the viral load was
brought under control during the ensuing 3 weeks, there was a coincident detection and
augmentation of Gag-specific T-helper-cell responses, analogous to those observed in LTNPs.

Immune Recovery Inflammatory Syndromes

The restoration of immune function with HAART can also have adverse consequences, due to
augmented immune responses to pathogens that are already present. Such immune
reconstitution syndromes are still poorly understood but have been reported in a variety of
settings. Encouragingly, emerging data suggest that most of these cases resolve with continued
therapy.[44] One report described 5 patients with CD4+ cell counts < 50 cells/mm3 who developed
fever and severe lymphadenitis within 1-3 weeks of initiating indinavir therapy.[45] Lymph node
biopsies showed focal lymphadenitis due to previously unsuspected Mycobacterium avium
complex infection. Because HAART is associated with increases in memory CD4+ cells, it is
possible that this syndrome is due to the expansion of mycobacterial-specific cellular immune
responses, which result in inflammation in the presence of a high bacterial burden.

An immune reconstitution syndrome termed "immune recovery vitritis" has been associated with
CMV retinitis.[46,47] In 1997, it was reported that some persons were developing CMV retinitis with
CD4+ cell counts well above the expected threshold of 50 cells/mm3. These patients had all
initiated HAART 4-7 weeks before the diagnosis of CMV retinitis, and it was initially interpreted
that HAART was not sufficient to prevent CMV retinitis despite rises in CD4+ cell counts.
However, in most of these patients, the duration of possible subclinical ocular infection before a
formal diagnosis of retinitis was not well established, and it has been conjectured that enhanced
immunity might actually be the reason why previously subclinical disease became clinically
apparent. Zegans and associates[48] reported transient vitreous inflammatory reactions in 8
persons receiving HAART, 6 of whom were known to have preexisting CMV retinitis. Vitreous
inflammation occurred between 1 and 8 months after initiating HAART, at a time when each of
the patients had experienced a substantial increase in CD4+ cell count. Of note, none of the
patients developed recurrent CMV retinitis during a 1- to 13-month follow-up. Another study also
documented vitritis associated with institution of HAART in patients with advanced disease, with
predominant posterior segment inflammation including cystoid macular edema and epiretinal
membrane formation leading to decreased visual acuity.[49] Overall, however, the dramatic
decrease in new cases of CMV retinitis that has been observed since the widespread use of
HAART suggests that the balance is being tipped in favor of persistent immune control of CMV.
CMV retinitis has been observed to regress with the institution of protease inhibitor therapy
alone in persons with advanced HIV infection, without specific anti-CMV therapy.[50]

Exacerbation of viral hepatitis has also been associated with institution of antiretroviral therapy
and can be particularly perplexing because of the difficulty in discriminating viral hepatitis from
drug-induced hepatotoxicity. This has been observed in persons with previously undiagnosed
HCV infection, as well as in persons with known viral hepatitis. The link to immune restoration is
provided by a report of persons who were HCV seronegative and HCV RNA positive and who
developed acute hepatitis with the institution of HAART, and went on to seroconvert.[51] In
addition, the lack of increases in serum HCV RNA levels at the time of acute hepatitis provides
additional support for the view that this syndrome is associated with restoration of HCV-specific
immunity. Since HCV coinfection occurs in 8% to 23% of HIV-infected persons, this syndrome
represents a management issue that is yet to be optimally resolved.

Overall, these and other syndromes of HAART-associated inflammatory disorders[52-56] should be


grounds for great optimism. The aforementioned cases indicate that functional immunity is being
restored with control of viremia and provide rationale for further attempts to augment pathogen-
specific immunity in HIV infection.

Key Points

Patients treated with HAART typically experience an early rise in memory CD4+ cells, followed by
a later rise in naive CD4+ cells. Recent studies suggest that the thymus may retain activity in
adult life, contributing to immune reconstitution. While improved immune responses to common
pathogens are seen (sometimes resulting in paradoxical inflammatory syndromes), enhancement
of HIV-specific responses is rare, possibly due to deletion of HIV-specific T-helper cells during
acute HIV infection.

Approaches to Immune-Based Therapy in HIV Infection

Attempts to reconstitute immunity in HIV infection have been attempted since the disease was
first characterized as an immunodeficiency disorder. Early approaches to immune reconstitution
included allogeneic and syngeneic bone marrow transplantation, donor lymphocyte infusions,
therapeutic vaccination, cytokine infusions, and combinations of these. Although transient
increases in delayed type hypersensitivity were occasionally observed, no consistent clinical
benefit could be found. Inability to control viremia doomed most of these early studies. The
prospects for immune reconstitution became more realistic with the advent of HAART, and
recent studies showing that the immune response to HIV can be manipulated to therapeutic
benefit[40] have set the stage for expanded approaches.

Immune Augmentation Following Early Treatment of Acute HIV Infection

The finding that viral load soon after infection predicts subsequent disease course[57] suggests
that the initial immune events may play a key role in the long-term outcome of infection. Studies
in both animals and humans with treated acute infection support this hypothesis.[37,58-60] By limiting
virus replication in acute infection, virus-specific T-helper-cell responses are induced and
maintained. New data indicate that this is likely due to limiting infection of HIV-1-specific CD4
cells as they transition from naive to memory cells.[31] There are now a number of studies
showing that early treatment augments HIV-specific CD4+ helper cell responses.[37,39] In contrast,
these responses do not typically increase in persons treated during the chronic phase of
infection.

The observed increase in virus-specific CD4+ T-helper cell responses is not mirrored by similar
effects on CTL. Indeed, early treatment of acute infection actually results in a statistically
significant decrease in the breadth and magnitude of CTL responses, compared with delayed
treatment.[43] This is a particularly puzzling finding given that virus-specific T-helper cell
responses increase, and persons usually have prolonged exposure to diminishing viral loads for
months after initiating therapy. It remains unclear why this is not sufficient to induce stronger
CTL responses.

In an interesting study worthy of special mention, 9 persons with acute HIV infection were
treated with HAART with or without concomitant cyclosporin for the first 8 weeks of therapy.[61] At
week 48, the proportion of HIV-specific interferon-gamma-secreting CD4+ T cells was
significantly higher in the group who received HAART plus cyclosporin than in those who
received HAART alone. The relevance of this finding to immune control could not be assessed
because the patients were maintained on antiretroviral therapy, but they are consistent with the
prediction of Douek and colleagues[31] that HIV-specific CD4+ cells would be preferentially
deleted, and the use of cyclosporin may have limited activation of these cells and thus resulted
in them being spared during the period of high viremia.

It is also important to consider the effects of early therapy on the induction of virus-specific
neutralizing antibody responses. In at least some cases, early treatment of acute HIV infection
has resulted in the generation of strong autologous neutralizing antibody responses, which are
rarely seen in persons with chronic progressive infection.[62] It is not clear why these responses
are induced, but it may be due to the fact that early therapy limits viral diversification, such that
neutralizing antibody responses have a chance to mature before the virus has evolved escape
mutations.[42] The extent to which such responses may be important clinically is not known.

The above data all refer to findings in HIV-infected adults. The immunologic impact of early
therapy on virus-specific immune responses in neonates is markedly different. Rather than
resulting in boosting of virus-specific T-helper cell responses, early and vigorous treatment
within the first month of life results in markedly diminished humoral and cellular immune
responses to HIV.[63] In most of these individuals, antibody responses completely disappear and
there are no detectable CTL responses. The extent to which such subjects might be able to
respond to HIV immunogens remains to be determined, but will be an important area of future
investigation.

Cytokine-Based Therapy

One of the most extensively studied immune-based therapies in HIV-infected persons is


interleukin 2 (IL-2). IL-2 is a cytokine secreted by activated T lymphocytes that regulates
lymphoid proliferation and maturation. Because its production is decreased in HIV infection, it
has been tested as a potential immunotherapeutic agent in infected persons. The first studies of
IL-2 therapy were initiated over a decade ago but were severely limited by toxicities because of
the high doses employed. However, decreasing the dose and using intermittent dosing led to
more tolerable clinical trials and to the observation that IL-2 therapy could dramatically increase
CD4+ cell counts in HIV-infected persons.

An uncontrolled pilot study of IL-2 revealed sustained increases in CD4+ cell counts in persons
with CD4+ cell counts greater than 200 cells/mm3 at baseline, but the immune activation
induced by IL-2 was also associated with transient increases in viral load.[64] In a larger
controlled trial, 60 HIV-infected patients with CD4+ cell counts > 200 cells/mm3 were
randomized to receive either IL-2 plus antiretroviral therapy (single or combination nucleoside
reverse transcriptase inhibitors) or antiretroviral therapy alone.[65] IL-2 was given for 5 days every
8 weeks by continuous infusion. After 6 cycles of treatment, CD4+ cell counts doubled from 428
± 25 cells/mm3 to 916 ± 128 cells/mm3 in persons on IL-2 therapy, whereas they dropped in
persons on antiviral therapy alone. Higher baseline CD4+ cell counts were associated with
greater responses to IL-2 therapy, and sustained increases in CD4+ cell counts could be
achieved with lower doses of IL-2 per day. There were no significant differences between the
groups in terms of viral load changes with treatment. The study was not powered to detect
potential differences in clinical benefit.

More recently, simplified regimens of IL-2 therapy have also been tested, with somewhat
promising results in terms of increased CD4+ cell counts and less toxicity. Persons randomized
to subcutaneous twice-a-day injections of IL-2 (1.5 or 7.5 MIU given every 4 or 8 weeks)
experienced persistent increases in CD4+ cell counts, particularly on the higher-dose, more
frequent regimen, in the absence of dose-limiting toxicities.[66] CD4+ cell counts were maintained
even when the dosing intervals were increased. Examination of the phenotype of expanded
cells in persons receiving IL-2 therapy has revealed selective expansion of specific subsets of
CD4+ cells, but these cells do not show evidence of increased expression of early (CD69) or
late (CD95) activation markers or evidence of recent proliferation (Ki67).[67] Much of the
expansion of CD4+ cells with IL-2 therapy is due to peripheral expansion rather than increased
thymic output, and these cells appear to have future replicative capacity because the new CD4+
cells do not have shortened telomers.[68] The increase in CD4+ cell counts on IL-2 therapy is
accompanied by an increase in the rate of CD4+ cell apoptosis when the IL-2 is withdrawn,
indicating that the sustained increase is the net result of increased production and decreased
cell death.[69] Whether IL-2-induced sustained increases in CD4+ cell counts have a beneficial
clinical effect will require further study.

Demonstration of the potential clinical benefit of IL-2 therapy remains an important goal. The
aggregate results of 3 clinical trials indicate that CD4+ cell increases can be maintained, that
viral loads are slightly lower, and that there may be a decreased risk of disease progression or
death in persons treated with IL-2. A recent clinical trial conducted at 8 sites in the United States
examined an intermittent regimen of subcutaneous IL-2 along with HAART and showed that the
combination resulted in lower viral loads and higher CD4+ cell count increases than HAART
alone.[70] However, whether the increases in CD4+ cell counts with IL-2 therapy translate directly
into heightened immunocompetence or true clinical benefit remains unclear. Progressive HIV
infection is associated with a more rapid loss of naive CD4+ cells than of memory cells. Immune
control of viral infections depends on a broad repertoire of immunocompetent cells, and HIV
infection leads to preferential deletion of parts of the T-cell repertoire. IL-2 administration is
associated with polyclonal increases in both naive and memory cells in HIV-infected persons,
but TCR analysis has demonstrated that the defects in the T-cell repertoire are not corrected by
IL-2 administration, at least during the short term.[14] If critical deletions in the CD4+ cell
repertoire cannot be corrected with IL-2 therapy, it is conceivable that use of IL-2 in conjunction
with other immune-based therapies should also be considered.

IL-2 has also been proposed as a mechanism for flushing virus from persistent reservoirs in
infected persons. Emerging data from a number of laboratories have provided evidence that
HIV-1 persists in CD4+ cells despite long-term viral suppression under HAART.[71,72] The virus
exists in this pool in a latent, integrated form, and retains the ability to produce infectious viral
particles when the cell becomes activated. Prolonged intermittent administration of IL-2 may
result in CD4+ cell activation, and in the presence of HAART the virions produced should not be
able to infect other cells. Indeed, in one matched but nonrandomized study of the frequency of
resting, latently-infected CD4+ cells in recipients of IL-2 plus antiretrovirals vs antiretrovirals
alone, a subset of patients in the former arm had a substantially lower amount of infectious virus
detected than did patients in the control group.[73] However, to date, when certain IL-2 recipients
from that study have voluntarily elected to discontinue HAART therapy as part of a clinical trial,
virologic relapse has occurred. This relapse suggests that the reservoir of latently infected cells
may have been diminished but certainly has not been eradicated. Moreover, since only around 1
in a million peripheral blood mononuclear cells (PBMCs) is latently infected, this strategy would
require that an enormous number of uninfected cells be activated to flush virus from a single
cell, and this degree of immune activation may have severely detrimental effects on the host.
This approach has demonstrated that toxicity is a major limiting factor.[74,75]

Although the idea of eradicating virus by driving it from sanctuaries has lost some appeal, there
are new data that provide encouragement that IL-2 may help to achieve a state of immunologic
control rather than eradication. The central immunologic defect described in HIV infection is the
relative lack of virus-specific T-helper-cell response, and one of the key cytokines produced by
virus-specific T helper cells is IL-2. In addition, as mentioned above, IL-2 may be able to flush
virus out from infected cells. How does one turn these 2 observations into a strategy to boost
immunity? There is no question now that naive cells appear to be generated in the course of
HAART, and it is reasonable to assume that these cells could be educated to recognize HIV.
However, in the course of HAART, as naive cells are being generated, there may be insufficient
antigen to trigger an effective immune response against HIV-1. In addition, there are likely to be
some virus-specific T-helper cells present in chronic infection that are not functioning properly
because of an IL-2 deficiency. Thus, at least theoretically, IL-2 may be particularly beneficial --
both by providing exogenous help to existing but dysfunctional T-helper cells and by stimulating
the production of viral antigen from latent reservoirs. However, a trial in which persons treated
with IL-2 plus antiretroviral therapy underwent treatment interruption failed to show enhanced
control of viremia compared with controls who received antiretroviral therapy alone.[70]

The remaining controversies with IL-2 therapy may not be resolved by the 2 large international
clinical trials in persons with chronic HIV infection. The Evaluation of Subcutaneous Proleukin in
a Randomized International Trial (ESPRIT) is a large ongoing randomized trial of subcutaneous
IL-2 plus HAART vs HAART alone in patients with CD4+ cell counts of at least 300 cells/mm3.[76]
The end point of this 4000-person, 23-site, 5-year trial will be to determine whether the addition
of IL-2 to combination antiretroviral therapy improves morbidity and mortality. A second IL-2 trial,
SILCAAT,[77] is a smaller phase 3 trial with a similar study design that is recruiting a more
advanced group of patients (those with CD4+ cell counts > 50 cells/mm3) and is starting at a low
dose of subcutaneous IL-2; this trial opened for enrollment in spring 1999. The SILCAAT trial
was recently terminated by Chiron, due in part to difficulties in administering a multinational trial
and in part due to an expected lack of sufficient end points in a timely manner.

Other cytokines may ultimately find their way into clinical trials. Among these is IL-12, which has
been shown to augment HIV-specific CTL function in vitro. [78] IL-12 is predominantly produced
by activated antigen-presenting cells and is thought to promote the development of Th-1 type
cellular immune responses. This type of response promotes CTL activity, which is clearly critical
in controlling viremia in infected persons. IL-12 also augments natural killer cell lysis and has
been shown to augment HIV-specific lymphocyte proliferation in vitro.[79] The fact that IL-12
production by lymphocytes is decreased in HIV-infected persons compared with uninfected
persons suggests that this cytokine might augment important immune function in HIV infection,
and in vitro studies show that it is able to augment HIV-specific CTL lysis.[78] IL-12 might thus
also be useful in expanding HIV-specific CTL for adoptive-therapy studies. Cytokines may also
find applicability as vaccine adjuvants, as recently shown for IL-12 with DNA vaccine in a murine
model of protective immunity against HSV-2.[80] One recent study in a murine model of chronic
viral infection suggests that exposure to IL-4 during T-cell stimulation results in more long-lived
CTL responses.[81] Further confirmation of such cytokine-induced effects on long-term immune
responses deserve further attention.

The overall cytokine milieu in HIV-infected persons may also be amenable to therapeutic
manipulation. It has been shown that progressive infection is associated with declining IL-2
production and increased IL-4 production.[82] The loss of recall antigen-stimulated responses in
progressive HIV infection has been reversed in vitro with anti-IL-4 antibody, and enhanced CTL
activity has been observed in IL-4-deficient mice.[83] These studies raise the question of whether
decreasing IL-4 production in vivo may have an immunologic benefit. Another possible approach
to immune reconstitution with cytokine therapy is suggested by a study showing that interferon
(IFN)-gamma can augment CD8+ cell immunity and clear Pneumocystis carinii pneumonia in a
CD4+ cell-depleted mouse model. Such results suggest that IFN-gamma may be able to
counterbalance the defect associated with CD4+ cell depletion. However, IFN-gamma therapy is
associated with known dose-dependent toxicities, and study of its overall clinical utility in HIV
has not been actively pursued.

Key Points

IL-2 regulates lymphoid proliferation and maturation. Intermittent low-dose IL-2 therapy results in
substantial increases in CD4+ cell counts, although their clinical significance remains unclear. In
theory, IL-2 may facilitate immune control of HIV infection by both aiding HIV-specific T-helper
cells and stimulating viral replication in latent reservoirs.

Adoptive Cell Transfers

Some of the earliest adoptive-therapy protocols involved the transfer of syngeneic lymphocytes
and/or bone marrow in twins discordant for HIV infection. Although there was no clear beneficial
effect, these early studies paved the way for further research.

In one of the first studies of adoptive transfer of autologous cells to infected persons, Klimas[84]
infused autologous CD8+ cells that had been expanded in vitro in the presence of
phytohemagglutinin and IL-2. Study subjects with CD4+ cell counts ranging from 50 to 200
cells/mm3 were given 5 infusions of their own cells that had been expanded in the laboratory
and were also given IL-2 infusion with the last cell dose. Although the trial showed a lack of
toxicity, no firm conclusions could be drawn regarding efficacy, and since these trials were done
before viral load assays became available, no effects on viral load were reported.

One of the first trials of adoptive therapy using HIV-specific CTL clones was performed by
Koenig and collaborators.[85] CTL clones specific for an epitope in Nef were established from a
person with chronic progressive infection. Expanded cells were then infused in the presence of
IL-2. Although such trials preceded the availability of quantitative viral RNA assays, there was
no clear drop in viremia by less sensitive methods despite the infusion of large numbers of cells.
However, they did provide evidence for immune selection pressure mediated by these cells, in
that sequencing of the endogenous virus following cell transfers showed the emergence of
mutations within the epitope as well as viruses containing full deletions of the epitope. The lack
of antiviral effect and the development of apparent immune escape suggested that
simultaneous infusion of IL-2 as well as the infusion of multiple clones with different specificities
might be useful. These initial studies suggested that the road to immune reconstitution was not
going to be straight.

The early study by Koenig and collaborators has been followed by additional attempts at
monoclonal and polyclonal cell transfers. Lieberman and colleagues[86] have established bulk
cultures of HIV-1-specific cells from infected persons and have shown that these can be safely
given back without toxicity. However, demonstration of an antiviral effect again has not been
forthcoming. Brodie and coworkers[87] established CTL specific for Gag epitopes from infected
persons and re-infused these, again in the absence of added cytokines. Biopsies revealed that
the infused cells migrated to sites of infected cells in lymphoid tissue. Moreover, the CTL
transfers were associated with transient decreases in PBMCs DNA viral load, but within days
the viral load returned to baseline. It was speculated that the lack of sufficient CD4+ T-helper-
cell function contributed to these transient decreases.

Further light has recently been shed on the issue of short-term survival of transferred CTL
clones, in studies from Tan and associates.[88] CTL clones specific for Gag and Pol epitopes
were established from a person with chronic HIV-1 infection, and re-infused when his viral load
was rising despite double nucleoside therapy. The fate of 1 of the clones in vivo was monitored
by staining it with an HLA class I-peptide tetramer, which had bound to the TCR of the infused
clone. The CTL transfer was well tolerated, but there was no decline in viremia or change in
CD4+ cell count. The lack of antiviral effect was concluded to be due to rapid apoptosis
(activation-induced cell death) of the infused cells in vivo, with over 90% of antigen-specific CTL
undergoing apoptosis at 48 hours after infusion. Although the precise mechanisms of apoptosis
were not defined, the authors speculate that lack of sufficient virus-specific helper-cell function
may have contributed and suggest that additional studies may be more successful if
administered in the presence of IL-2.

In contrast to transferring antigen-specific cells to infected persons, some trials have attempted
to augment immunity by infusing antigen-presenting cells that have been pulsed with
immunogenic peptides.[89] Partially HLA-matched dendritic cells obtained from uninfected
siblings were incubated with immunogenic HIV-1 peptides, in order to load class I molecules
with viral peptide. These cells were then infused and were largely well tolerated. Although some
fluctuations in immune responses were noted following infusions, there was no statistically
significant difference observed over the course of the trial, and viral loads were not reduced.
Less specific means of immune restoration have been attempted in a cohort in Australia, in
whom autologous PBMCs were cryopreserved in the early stages of asymptomatic infection.
These frozen cells were then thawed and infused as CD4+ cell counts began to decline.
Augmentation of CD4+ cell count was seen in some persons, and viral loads were reduced by
one-half log in 2 of the 4 persons tested. Whether these infusions had a lasting clinical benefit
could not be addressed by the study design.

Arguably the most promising results of immunotherapy studies in AIDS virus infection come
from recent studies of adoptively transferred dendritic cells pulsed with inactivated virus. In
these studies in monkeys with chronic SIV infection, autologous dendritic cells were isolated
and matured ex vivo, and then pulsed with aldrithiol-2 inactivated SIV. When these cells were
subsequently infused into chronically infected animals in the absence of antiviral therapy, a 100-
to 1000-fold drop in viremia was observed.[90] These results, if they can be confirmed, offer
substantial support for immune based therapy, and suggest that the defect may be in the
induction phase of the immune response.

Another approach to adoptive immunotherapy is the infusion of expanded CD4+ cells. Levine
and collaborators[91] have used a novel stimulation strategy in vitro to expand CD4+ cells that are
putatively free of infectious virus. Their protocol involves the use of anti-CD3 and anti-CD28
monoclonal antibodies to stimulate the expansion of CD4+ cells. This stimulation strategy
renders the cells resistant to HIV infection by altering the expression of CCR5, a coreceptor for
viral entry, at the cell surface.

A recently complete clinical trial also provided some optimistic results.[92] Polyclonally expanded
peripheral blood CD4+ cells were given as infusions of up to 30 billion activated CD4+ cells to
persons infected with HIV who were receiving stable antiretroviral therapy. This led to detectable
dose-dependent increases in CD4+ cells, and the phenotype of these cells was notable for a
decrease in CCR5 expression, suggesting reduced susceptibility to infection with HIV. Over
time, the frequency of CD4+Ki-67+ cells increased whereas CD4+ T cells containing TRECs
decreased, consistent with in vivo expansion. Further studies will be needed to determine the
overall impact on viral replication. Additional planned approaches include the in vitro expansion
of antigen-specific CD4+ cells, which may help to correct the defect in HIV-specific T-helper
cells seen in the majority of persons with chronic progressive infection. At least one study
examining persistence of adoptively transferred, gene vector transduced CD4+ cells has shown
striking persistence of these cells in vivo, offering support for such approaches.[93]

Therapeutic Vaccination

Early trials of therapeutic vaccination yielded disappointing results, but because these vaccines
were administered in the pre-HAART era, it is perhaps not surprising that the trials failed to
show a clinical benefit.[94] Cellular activation is the anticipated result of immunization, but in the
presence of infectious virus these activated cells become preferential targets for the virus.
However, with the advent of HAART it is now possible to administer vaccines under cover of
more potent antiretroviral therapy and to protect activated cells from becoming infected and
potentially deleted. Together with the fact that numerous studies suggest that there is a
deficiency of antiviral cells in vivo, this provides a compelling rationale for this approach.

One of the most extensively studied therapeutic vaccine candidates is Remune. This is an
inactivated whole virus vaccine that has been largely depleted of the envelope protein during
the processing and inactivation steps involved in its synthesis.[95.96] The vaccine is derived from a
virus originally obtained in Zaire and contains a clade A envelope and clade G gag. It has now
been administered to more than 3000 persons. Because this trial was initiated during the time
that combination antiviral therapy became the standard of care, a significant proportion of
persons receiving the vaccine were on maximally suppressive antiviral therapy when it was
given. This vaccine has been shown to induce Gag-specific T-helper-cell responses in HIV-
infected persons, which were surprisingly robust in some vaccine recipients.[97,98] Whether these
responses provide a clinical benefit is not yet clear, but the issue is certainly worthy of further
investigation, since Gag-specific T-helper-cell responses have been associated with control of
viremia in chronically infected persons.

A number of trials of envelope-based vaccines have been completed, with largely disappointing
results. Part of the problem may be the lack of immunogenicity of the currently available
recombinant proteins, which do not represent the oligomeric structure of the native protein in
vivo. The antibody responses induced by HIV envelope protein vaccines to date are not broadly
cross-reactive with the many different strains of virus seen in the population at large. Some
envelope vaccines have induced HIV-1-specific T-helper cells,[99] but the ability of envelope-
based vaccines, at least as currently formulated, to protect against infection by primary viral
isolates from infected individuals is likely to be limited. More potent and broadly directed
neutralizing antibodies have recently been induced using a new approach.[100] In those studies,
"fusion-competent" immunogens have been generated by fixing cells in the transient stage of
fusion, involving the interaction of envelope, CD4, and coreceptor. These immunogens are more
representative of functional envelope in active infection. In a murine model, high levels of
broadly cross-reactive neutralizing antibodies were induced to these fusion-competent
immunogens. Whether induction of these responses would be beneficial in infected persons
deserves investigation, but clinical trials have not yet been designed.

In addition to recombinant proteins, other approaches are being pursued or will soon be
pursued. Canarypox vectors, which are similar to vaccinia virus but have a limited ability to
replicate in human cells, are being tested in pilot studies in humans.[99] In an initial study of
persons treated during acute HIV infection who were then immunized with a canarypox vector
expressing multiple HIV proteins followed by boosting with recombinant gp160,[101] augmentation
of HIV-specific antibody responses was observed in 13 of 14 subjects, as well as some
increases in T-cell proliferative responses in 9 of 14 subjects. In addition, 11 of 14 persons had
increases in CD8+ T-cell responses as determined by Elispot assay. Studies in seronegative
persons have shown that these vectors are able to induce T-helper cell and CTL responses, as
well as antibodies, and these responses are more robust in regimens that include a boost with
recombinant protein vaccines. This and other DNA vaccines are currently being studied in
phase 1 dose-escalating trials, as are combination approaches involving multiple different
immunogens. Recent studies of DNA vaccines in macaque models suggest that potent CTL
responses might be induced by such vectors, alone or in combination with adjuvants or
cytokines.[102]

Another promising vector is Venezuelan equine encephalitis virus. In early studies in macaques,
significant levels of protection from disease have been noted in both SIV and Marburg virus
model systems when used as a prophylactic vaccine.[103,104] It is important to note that there are
no data yet to indicate that therapeutic vaccination in HIV infection has a beneficial effect, but
since most early studies from which data are available were performed in the pre-HAART era,
these approaches deserved renewed attention.

Key Points

Studies of adoptive transfer of CD8+ cells have been hampered by poor cell longevity and
apparent immune escape. Other experimental approaches include transfers of antigen-
presenting cells or expanded numbers of CD4+ cells. Early studies of therapeutic vaccines were
disappointing, but further study in combination with HAART is now warranted. Remune has been
associated with improved HIV-specific immune responses, but their clinical significance remains
uncertain.

Interruptions in Therapy to Augment Immunity


A potential alternative to therapeutic vaccination is the use of the patient's own virus as a means
of augmenting immunity. Before even discussing this, it is important to stress that this approach
should only be tried in the context of very carefully controlled clinical trials. It is also extremely
important to separate those cases treated initially during the acute phase of infection from those
treated during the chronic phase of infection, since the groups appear to respond quite
differently.

It has long been known that live-virus vaccines are among the most effective vaccines available.
The availability of HAART theoretically offers the opportunity to give a regulated dose of the
patient's own live virus as a vaccine. A number of anecdotal cases of persons treated in the
acute stage of HIV infection offered reason for cautious optimism that such an approach might
be beneficial in boosting immunity. One person treated early following acute infection initially
had a dramatic decrease in viral load, but a few weeks into therapy he developed an
intercurrent illness that prompted him to discontinue his antiretrovirals.[105] This resulted in a rise
in plasma viremia, which was rapidly brought under control by reinstitution of antiretroviral
therapy. He then transiently discontinued therapy again without a rebound in viral load, and after
a total of 6 months, he discontinued therapy permanently. After 24 months of follow-up, viremia
remained controlled, with HIV-1 RNA persistently < 1000 copies/mL; this control was associated
with persistent and vigorous T-helper-cell and CTL responses. A second report of an association
between treatment interruption and prolonged immune control was again confined to persons
who received treatment in acute HIV infection, went on to take therapy intermittently, and
ultimately came off therapy.[106]

Recently, data have been reported from a prospective, nonrandomized clinical trial of early
treatment of acute infection followed by supervised treatment interruption. Our initial study[40]
included 8 subjects started on HAART before seroconversion or within 180 days of infection.
Viremia was well contained in all, including those who had HIV-1 RNA levels > 50 million
copies/mL at the time of initiation of therapy. After a mean of 2 years on therapy, treatment was
discontinued. Viremia recurred in all, but all were able to at least transiently control viral
replication < 5000 copies/mL after 1 or 2 treatment interruptions. At the time of the initial
publication of these studies, 3 of the 8 subjects had never met criteria to restart medication
(namely, HIV-1 RNA > 5000 copies/mL for 3 consecutive weeks, or a single HIV-1 RNA rebound
to > 50,000 copies/mL). In each of these 3 persons, an initial peak in viremia was subsequently
suppressed, and viral load was suppressed to < 500 copies/mL up to nearly a year after
infection. The other 5 persons all had viral rebound necessitating reinstitution of therapy, and
HAART led to rapid control of viremia. After prolonged suppression of viremia, therapy was
again interrupted. All 5 rebounded to lower peak levels than at the first interruption, and all went
on to suppress viremia for at least a few months.

In this cohort of persons with treated acute HIV infection, evaluation of immune responses
indicated that T-helper-cell responses persisted after stopping therapy, and CTL responses
increased in both breadth and magnitude. These data indicate that the immune response to HIV
can be augmented in natural infection, and that this enhanced control is associated with
enhanced cellular immune responses. Similar findings have been reported in the SIV model as
well,[107] further supporting the findings in humans. It should be noted, however, that although
increases in immune control have been observed, the durability and ultimate long-term clinical
benefit of enhanced control is far from clear.

The major questions arising from these studies of STI in acute infection are whether a clinical
benefit is achieved and what the duration of control might be. In our own studies we have now
observed late breakthroughs in viremia after control for 1 year or longer. Although one of these
cases was associated with superinfection with a second B clade virus,[108] others appear to be
due to gradual loss of control of the original virus (unpublished observations). In the majority of
persons there is evidence of a gradual increase in viremia over time, as well as a gradual
decrease in CD4+ cell count, indicating that immune control is insufficient in most cases.
Whether the transient period of immune control in these persons translates into a clinical benefit
is not clear, and will likely be answered by a larger randomized clinical trial currently being
initiated. Those persons who do experience a recurrence of viremia offer the opportunity to
dissect the correlates of loss of control of viremia, and should provide important insights into the
level of immunity required for control of viremia. Detailed dissection of immune responses in
these persons as well as further longitudinal follow-up and expanded controlled trials will be
necessary to determine the clinical benefit of STI. In the meantime this is not an approach that
should be taken except in the context of clinical trials.

The potential role of therapy interruption in chronic infection is much less clear. To date there
have been no anecdotal cases of persistent control of viremia following interruption of therapy
instituted during the chronic phase of infection; indeed, it is not even clear how long after acute
infection treatment can be initiated and still lead to meaningful augmentation of immune function
after stopping therapy. Numerous trials STI have now been reported in chronic infection,[109-113]
and there are as yet no reports of sustained control induced by this approach. Detailed studies
examining both lymph nodes and peripheral blood in persons undergoing STI in chronic
infection showed that although there was evidence of increases in CD8+ T-cell responses,
these represented expansion of preexisting responses rather than induction of new responses.
A large clinical trial of repeated STI in chronic infection showed that pretreatment viral load
correlated with post-STI viral load, and although there was some increase in immune responses
with STI, the quality and quantity of these responses did not change appreciably. Moreover,
HIV-specific CD4+ T-cell responses were only maintained after STI in those persons who had
low pretreatment viral loads.[114] There have been reports of recurrence of an acute infection
syndrome in persons who have stopped therapy.[115,116]

Another issue to be addressed in these studies of treatment interruption as a way to augment


anti-HIV immunity is whether this facilitates the development of drug resistance. Data are limited
at this point, but this is a major concern. Since early treatment prevents viral diversification,[43,117]
the underlying viral quasispecies diversity is expected to be less, which would be expected to
limit the development of antiviral drug resistance. Our own data indicate that clinically significant
drug resistance has not been induced in persons who were treated initially in acute infection,[118]
but concerns remain, particularly regarding this approach during chronic infection.[119] Ongoing
carefully controlled clinical trials will determine whether repeated transient interruptions in
therapy lead to the development of antiviral drug resistance.[120]

Passive Antibody Therapy

Passively transferred hyperimmune serum has been tested in monkey, murine, and human
models of immunodeficiency virus infection. In monkeys given hyperimmune SIV serum,
protection from oral inoculation can be achieved, but this requires that the serum be
administered before the time of viral exposure.[121] Similar results have been achieved using
pools of strongly neutralizing antibodies.[122] By contrast, no protection is observed when serum
is administered 3 weeks after exposure to virus.[121] In another study of postexposure
prophylaxis, earlier administration of hyperimmune serum was shown to delay disease
progression.[123,124] This likely reflects a lowering of viremia during the critical early stage of
infection and therefore cannot be interpreted to mean that passive antibody therapy would be
effective in chronic HIV infection. In studies in SCID-Hu mice, passive transfer of a monoclonal
neutralizing antibody led to protection when administered either 1 hour before or 4 hours after
challenge with HIV, but no effect was seen when the antibody was administered in patients with
established infection.[125]

Studies in humans have not yet shown a statistically significant benefit of passively transferred
anti-HIV serum beyond the benefit that is obtained with zidovudine alone.[126] The passive
antibody approach may also be less effective at preventing transmucosal infection.[127] The use of
cocktails of neutralizing antibodies with different specificities has been shown to augment
antiviral activity in vitro, and studies performed in animal models indicate that this is an attractive
avenue for future investigation,[128,122,129-132] particularly in settings where the timing of exposure is
known[133] and in regard to whether more broadly cross-neutralizing antibodies can be developed.

Gene Therapy

Genetic manipulation of cells to convert them into anti-HIV CTL has been achieved,[134] and a
clinical trial is presently under way testing the efficacy of these cells in persons with chronic HIV
infection. Lymphocytes are obtained from infected persons and transduced with a vector that
results in expression of the external portion of the CD4 molecule linked to the intracellular
portion (the zeta chain) of the T-cell receptor. When the CD4 portion encounters an infected cell
expressing HIV envelope on the cell surface, signaling through the intracellular portion of the T-
cell receptor converts the transduced cell into a cytotoxic T cell, delivering a lethal hit to the
infected cell. These cells inhibit HIV replication in vitro equally as well as HIV-1-specific CTL
clones derived from infected persons.[135] The clinical trial will determine whether they have an
effect on the viral set point or on viral reservoirs. A number of other gene therapy strategies,
utilizing a variety of different transduction vectors and different antiviral constructs, have also
been proposed or are already under way. Such trials often incorporate gene-marking
capabilities that, at the very least, have provided significant insights into the fate (ie, kinetics,
trafficking, and durability) of transduced lymphocytes after they are infused into the recipient
hosts.

Key Points

In some cases, therapy interruptions have been associated with augmented HIV-specific immune
responses and prolonged viral remission; in most cases, however, viremia rapidly rebounds.
Passive antibody therapy has not been shown to have clinical benefits. Gene therapy
approaches for creating lymphocytes with anti-HIV activity are being studied.

Case Study: Part 4

The patient was maintained on antiretroviral therapy for 18 months, during which time his viral
load remained < 50 copies/mL and he maintained his adherence to triple-drug therapy. His T-
helper-cell responses and CTL responses remained robust for the first year and then started to
decline. The CTL responses were tested by Elispot assay, tetramer assay, and by limiting dilution.
The Elispot assay indicated CTL directed at 2 different Gag peptides. The tetramer assay,
currently available only for measurement of responses to an immunodominant A2-restricted
epitope in p17, was negative.

On the basis of persistent immune responses, he was entered into an experimental protocol to
discontinue therapy to determine whether the magnitude of immune responses was sufficient to
control viremia. After stopping therapy, viral load was undetectable for the first 10 days and then
rose to greater than 50,000 copies/mL during the next week, necessitating retreatment per the
experimental protocol. Viral load rapidly decreased to less than 50 copies/mL, and both CTL and
T-helper-cell responses increased compared with baseline.

After HIV RNA had remained less than 50 copies/mL for a total of 3 months, therapy was again
interrupted. Viral load was detectable earlier, but rose to a lower peak value of 30,000 copies/mL
and then spontaneously declined. During the next 6 months the viral load remained consistently <
5000 copies/mL, and at times was less than 500 copies/mL. This apparent relative control of
viremia was associated with increases in breadth and magnitude of CTL responses, and
maintenance of T-helper-cell responses.

Conclusions

The next frontier of AIDS treatment is immune-based therapy. It is clear that viral eradication will
not be achieved easily with the antiviral agents currently available. The ability of augmented
HIV-specific immunity to enhance immune control of HIV has been demonstrated within the last
few years. However, the durability of these responses, as well as the potential to achieve
clinically meaningful immune augmentation in either acute or chronic HIV infection, remains to
be determined. Nevertheless, promising early results in both SIV and HIV infection suggest that
the goal of immune-mediated containment of HIV is realistic and should be pursued with vigor.
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Authors and Disclosures

Author

Bruce D. Walker, MD
Director, Partners AIDS Research Center, Massachusetts General
Hospital and Harvard Medical School, Boston, Massachusetts

Disclosure: Dr. Walker has disclosed that he has acted as a


consultant for Genzyme, GlaxoSmithKline, and Abbott. He has also
reported that he has served on the speaker's advisory boards of
Agouron and Point Therapeutics. Dr. Walker has not discussed any
investigational products or unlabeled uses of any commercial
products in this article.

Editor

Craig Sterritt

Site Editor/Program Director, Medscape HIV/AIDS, Medscape Infectious Diseases

Disclosure: Craig Sterritt has no significant financial interests or relationships to


disclose.

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