CLINICAL SCIENCE

Pathogenesis
Intinya :
Virus masuk ke sel: membutuhkan CD4 and co-receptors, yang merupakan
reseptor untuk chemokines; involves pengikatan viral gp120 dan fusi dengan cell
mediated by viral gp41 protein; target seluler utama: CD4+ helper T cells,
macrophages, DCs (Dendritic Cells)
Viral replication: integrasi dari provirus genome dengan host cell DNA;
triggering of viral gene expression by stimuli that activate infected cells (e.g.,
infectious microbes, cytokines produced during normal immune responses)
Progression of infection: acute infection of mucosal T cells and DCs; viremia
with dissemination of virus; latent infection of cells in lymphoid tissue; continuing
viral replication and progressive loss of CD4+ T cells
Mechanisms of immune deficiency:
Loss of CD4+ T cells: T cell death during viral replication and budding
(similar to other cytopathic infections); apoptosis occurring as a result of
chronic stimulation; decreased thymic output; functional defects
Defective macrophage and DC functions
Destruction of architecture of lymphoid tissues (late)

Mechanism of T-cell Depletion in HIV Infection

Loss of immature precursors of CD4+ T cells, either by direct infection of

thymic progenitor cell sor by infection of accesory cell that secrete
cytokines essential fot CD4+ maturation. Th result is decreased production
of CD4+ T cells
Chronic activation of uninfected cells by HIV antigens or by other
concurrent infected microbes may lead to apoptosis of T cells. Because of
this activation-induced death of uninfected cells, the number of T cells
that die may be much greater than the number of HIV-infected cells.
Infection of various cells in lymphoid tissues may disrupt the normal
architecture, leading to impaired immune response
Fusion of infected and uninfected cells cause formation syncytia (giant
cells). In tissue culture, gp120 expressed on productively infected cells
binds to CD4 molecules on uninfected T cells, followed by cell fusion,
ballooning, and death within a few hours. This property of syncytia
formation is confined to the X4 strain of HIV.
Uninfected CD4+ T cells may bind soluble gp120 to the CD4 molecule,
leading to aberrant signaling and apoptosis.
nfected CD4+ T cells may be killed by HIV-specific CD8+ CTLs.

Monocytes/Macrophages in HIV Infection

Besides providing a portal for initial transmission, monocytes and macrophages are viral reservoirs
and factories, whose output remains largely protected from host defenses. Circulating monocytes also provide a
vehicle for HIV transport to various parts of the body, particularly the nervous system. In late stages of HIV infection,
when the CD4+ T cell numbers are massively depleted, macrophages remain a major site of continued viral
replication.
Although the number of HIV-infected monocytes in the circulation is low, their functional deficits (e.g., impaired
microbicidal activity, decreased chemotaxis, abnormal cytokine production, diminished antigen presentation capacity)

have important bearing on host defenses.

DCs in HIV Infection

In addition to macrophages, two types of DCs also are important targets for the initiation and maintenance of HIV
infection: mucosal and follicular DCs.
Mucosal DCs capture the virus and transport it to regional lymph nodes, where CD4+ T cells are infected.
Follicular DCs in the germinal centers of lymph nodes are important reservoirs of HIV. Although some follicular DCs
are infected by HIV, most virus particles are found on the surface of their dendritic processes, including those bound
to Fc receptors through HIVanti-HIV antibody complexes.
The antibody-coated virions localized to follicular DCs retain the ability to infect CD4+ T cells. HIV infection of
macrophages and DCs also may impair the functions of these cell populations, with secondary effects on T cell
responsiveness.

B Cells and Other Lymphocytes in HIV Infection

The HIV gp41 itself can promote B cell growth and differentiation, and HIV-infected macrophages produce increased
amounts of IL-6, which enhances B cell proliferation. Despite the presence of spontaneously activated B cells,
patients with AIDS are unable to mount antibody responses to newly encountered antigens. Not only is this
attributable to deficient T cell help, but antibody responses against T cellindependent antigens are also suppressed,
suggesting additional B cell defects. Impaired humoral immunity renders these patients susceptible to encapsulated
bacteria (e.g., S. pneumoniae, H. influenzae) that require antibodies for effective opsonization andclearance.
CD4+ T cells play a pivotal role in regulating the immune response: they produce a plethora of cytokines, chemotactic
factors, and hematopoietic growth factors (e.g., granulocyte-macrophage colony-stimulating factor).
Therefore, loss of this master cell has ripple effects on virtually every other cell of the immune system.

Natural
History
Clinical Course

and

The acute phase represents the initial response of an immunocompetent

adult to HIV infection. Clinically, this phase typically manifests as a selflimited illness that develops in 50% to 70% of affected persons 3 to 6
weeks after infection; it is characterized by nonspecific symptoms
including sore throat, myalgia, fever, rash, and sometimes aseptic
meningitis. This phase is also characterized by high levels of virus
production, viremia, and widespread seeding of the peripheral lymphoid
tissues, typically with a modest reduction in CD4+ T cells. Soon, however,
a virus-specific immune response develops, evidenced by seroconversion
(usually within 3 to 17 weeks of exposure) and by the development of
virus-specific CD8+ CTLs. As viremia abates, CD4+ T cells return to nearly
normal numbers. However, the reduction in plasma virus does not signal
the end of viral replication, which continues within CD4+ T cells and
macrophages in the tissues (particularly lymphoid organs).
The middle, chronic phase represents a stage of relative containment
of the virus. The immune system is largely intact at this point, but there is
continued HIV replication that may last for several years. Patients either
are asymptomatic or develop persistent lymphadenopathy, and minor
opportunistic infections such as thrush (Candida) or herpes zoster. During
this phase, viral replication in the lymphoid tissues continues unabated;
thus, there is no true microbiologic latency in HIV infection. The extensive
viral turnover is associated with continued loss of CD4+ cells, but a large
proportion of the CD4+ cells is replenished and the decline of CD4+ cells
in the peripheral blood is modest. After an extended and variable period,
the number of CD4+ cells begins to decline, the proportion of the
surviving CD4+ cells infected with HIV increases, and host defenses begin
to wane. Persistent lymphadenopathy with significant constitutional
symptoms (fever, rash, fatigue) reflects the onset of immune system
decompensation, escalation of viral replication, and the onset of the
crisis phase.
The final, crisis phase is characterized by a catastrophic breakdown of
host defenses, a marked increase in viremia, and clinical disease.
Typically, patients present with fever of more than 1 months duration,
fatigue, weight loss, and diarrhea; the CD4+ cell count is reduced below
500 cells/L. After a variable interval, serious opportunistic infections,
secondary neoplasms, and/or neurologic manifestations (so-called AIDSdefining conditions) emerge, and the patient is said to have fullblown
AIDS. Even if the usual AIDS-defining conditions are not present, Centers
for Disease Control and Prevention (CDC) guidelines define any HIVinfected person with CD4+ counts of 200 cells/L or less as
having AIDS.

STADIUM HIV
Stadium klinis HIV/AIDS untuk remaja dan dewasa
terkonfirmasi menurut WHO:
1. Stadium 1 (asimtomatis)
Asimtomatis
Limfadenopati generalisata
2. Stadium 2 (ringan)
Penurunan berat badan <10%

dengan infeksi HIV

 Manifestasi mukokutaneus minor: dermatitis seboroik, prurigo, onikomikosis.

ulkus oral rekurens, keilitis angularis, erupsi papular pruritik
Infeksi herpes zoster dalam 5 tahun terakhir
Infeksi saluran napas atas berulang: sinusitis, tonsiiitis, faringitis, otitis
media.
3. Stadium 3 (lanjut, advanced)
Penurunan berat badan >10% tanpa sebab jelas
Diare tanpa sebab yang jelas >1 bulan
Demam berkepanjangan (suhu >36,7 C, intemiten/konstan) >1 bulan
Kandidiasis oral persisten;
Oral hairy Ieukoplakia;
Tuberkulosis paru
Infeksi bakteri berat: pneumonia, piomiositis, empiema, infeksi tulang/sendi,
meningitis, bak- teremia;
Stomatitis/gingivitis/periodontitis ulseratif nekrotik akut
Anemia (Hb < 8 g/dL) tanpa sebab jelas, neutropenia (< 0,5x10^9/L) tanpa
sebab jelas. atau trombositopenia kronis (< 50x10^9/L) tanpa sebab yang
jelas.
4. Stadium 4 (berat. severe)
HIV wasting syndrome
Pneumonia akibat Pneumocystis carinii
Pneumonia bakterial berat rekuren
Toksoplasmosis serebral
Kriptosporodiosis dengan diare >1 bulan
Sitomegalovirus (cytomegalovirus, CMV) pada orang selain hati, limpa, atau
kelenjar getah bening
Infeksi herpes simpleks mukokutan (>1 bulan) atau viseral
Leukoensefalopati multifokal progresif
Mikosis endemik diseminata
Kandidiasis esofagus, trakea, atau bronkus
Mikobakteriosis atipik, diseminata, atau paru
Septikemia Salmonella non-tifoid yang bersifat rekuren
Tuberkulosis ekstrapulmonal
Limfoma atau tumor padat terkait HIV
Sarkoma Kaposi
Ensefalopati HIV
Kriptokokosis ekstrapulmoner termasuk meningitis
Isosporiasis kronik
Karsirnoma serviks invasif
Leismaniasis atipik diseminata
Nefropati terkalt HIV simtomatis atau kardio miopati terkait HIV simtomatis
Clinical Features

Opportunistic Infections

 Neoplasms
Pasien dengan AIDS
memiliki insidensi yang
tinggi terhadap tumor
tertentu, terutama Kaposi
sarcoma, B cell non-Hodgkin lymphomas, dan cervical cancer pada wanita.

CNS Involvement

Involvement of the CNS is a common and important manifestation of AIDS. At

autopsy, 90% of patients are found to have some form of neurologic
involvement, and 40% to 60% have clinically evident neurologic dysfunction.
These include an aseptic meningitis occurring at the time of seroconversion,
vacuolar myelopathy, peripheral neuropathies, and (most commonly) a
progressive encephalopathy clinically designated the AIDS dementia complex.
Source : Robbins 9th Edition, WHO, Harrison