HIV/AIDS Epidemiology, pathogenesis, prevention,

treatment and genomic medicine.

Alessandro Toso

ABSTRACT

Introduction: More than 38.6 million people live with human

immunodeficiency virus (HIV) in the world. The Virus was identified and isolated
in 1984.The identification of HIV allowed us to develop new strategies for HIV
prevention and design efficient antiretroviral therapies .
The Virus: On HIV-1 envelop there are two molecules,gp120 and gp41.After the
interaction of these two glycoproteins with CD4+ cells, two co-receptors CCR5
and CXCR4 are essential for the entry of the virus core in the cells. The viral
genome is reverse transcribed into DNA. Some mutation in genes like the delta32
deletion in CCR5 can give a HIV-resistant immune system.
Therapies: The best therapy in the meantime is the use of antiretroviral
drugs(ART),which helps to suppress the viral replication and to preserve the
immunologic function. New gene therapies ,that involve the CCR5 gene, the TAT
gene of HIV virus, can displace the ART therapies in the near future.
Conclusions: Advances in genomics have led to mounting expectations in regard
to their impact on health care and disease prevention.
Humans show remarkable variation in vulnerability to infection by HIV-1 and
specially in the clinical outcome . The studies about the CCR5 mutations, and the
virus genome ,can soon free patient from a drug therapy.
Introduction

The AIDS epidemic began in June 1981, when a report entitled “ Pneumocystis
carinii Pneumonia-Los Angeles” appeared in the Morbidity and Mortality Weekly
Report (MMWR) ,the bulletin of Center for Disease Control (CDC) .(1)
The case involved five young homosexual men affected by Pneumocystis Carinii
pneumonia, a rare infection, occurring only in patients with underlying immune
deficiency, in the University of California at Los Angeles (UCLA) Medical Center.
After many similar reports, both Gallo’s laboratory and Montagnier’s laboratory
tried to isolate in culture the AIDS virus. The collaboration among these groups of
scientists and clinicians was essential to achieve the goal and only three years later,
the causative agent named human immunodeficiency virus type 1 (HIV1) was
identified .
The causative relation between HIV 1and AIDS was accepted by the scientific and
medical community in 1984 and in 1985 a blood test for HIV was available.
The identification of HIV allowed us to eliminate HIV transmission through the
transfusion of blood ,to create rational policies for prevention and desing efficient
therapies.
Nowadays the main problem is that an estimated 38.6 million people live with
HIV-1, while about 25 million have died already.
Although Southern Africa remains the epicentre of the pandemia,today there's no
region of the world untouched by this disease.

(figura 1) da lancet 2006;368:489-504

Sexual transmission remains the dominant mode of transmission and accounts for
about 85% of all HIV1 infections .Outside Africa HIV 1 infections are acquired
also through injecting drug use. Sexual relationships ,partner change ,sexual
practices ,the presence of other sexually transmitted disease ,and population
mobility patterns increase the probability of HIV 1 acquisition.
Occupational exposures of health care workers to HIV infected blood and body
fluids through ipercutaneous inoculation is reported.
Furthemore HIV is transmitted through blood from mother infected to infant.

Virus Characteristics

Based on their genetic make-up ,HIV -1 viruses are divided into three different
groups. HIV-1 viruses has diversified into at least nine subtypes and many
circulating recombinant forms ,which encode genetic structures from two or more
subtypes. The continuously evolving HIV1 viral diversity poses an immense
challenge to the development of any preventive or therapeutic intervention.

Pathogenesis of HIV

The HIV 1 life cycle is complex. The HIV 1 in the early steps gains access to cell
without causing immediate lethal damages but the entry process can stimulate
intracellular signal cascades ,which in turn might facilitate viral replication .
On the HIV1 envelop the are two molecules : the external glycoprotein gp120 and
the transmembrane protein gp41.
During the entry process gp120 attaches to the cell membrane by first binding to
the CD+4 receptor. Subsequent interactions between virus and chemokine co-
receptors CCR5 and/or CXCR4 trigger irreversible conformational changes and by
pore formation the virus core is released in the cytoplasm .Than the viral genome
is reverse transcribed into DNA by the virus’ own reverse transcriptase enzyme.
Viral variants can be generated during this process, because of the no proofreading
activity of the reverse transcriptase.
Human immunodeficiency virus 1 requires a second receptor, either CCR5 ,or CX
chemiokine receptor 4(CXCR4),to enter CD4+ cells.
Some Virus may exclusively use either CRC5 (virus type R5) or CXCR4 (virus
type X4) or may use both ( virus dual-tropic).
Most transmitted variants are R5, and R5 virus is predominant early in the
Infection.CXCR4-tropic viruses appear in late stages of infection, and are
associated with the disease progression.
Infections with two o more genetically distinct viruses could lead to new
recombinant viruses.

Human genomics and infectious diseases

The epidemiology, pathogenesis and therapeutics of HIV-1 infection are certainly

influenced by human genomics.
Humans show remarkable variation in vulnerability to infection by HIV1 and in
the clinical outcome after infection.
Two groups of long- term non- progressors and highly exposed persistently
seronegative individuals have been studied to identify innate and acquired
protective determinants.
The most relevant genetic variants include those of major histocompatibility
complex (MCH) genes, as well as others variants, in the chemokine receptors
CCR5 CCR2.
One example of this is a 32- bp deletion in a chemokine receptor gene CCR5.
Persons who are homozygous for this deletion are almost completely resistant to
infection whit HIV1 and those who are heterozygous for the deletion have slower
progression from infection to AIDS.These effects arise because CCR5 is an
important part of the mechanism by which HIV enters the cell.
In sub-Saharan Africa, where HIV is highly endemic ,genetic factor that delay HIV
disease progression will likely become enriched in the population whereas those
which promote rapid progression to AIDS will decline.

Therapies
Since 1987 at least 20 antiretroviral compounds have been approved for clinical
use, numerous associations between human genetic variants and antiretroviral
treatment (ART) responses have been reported.
Most of antiretroviral drugs approved by US Food and drug Administration, target
the viral reverse transcriptase or protease.
The goal of treatment is to decrease the morbidity and mortality of the infection.
The therapy helps to increase disease-free survival through maximal suppression of
viral replication and preservation of immunologic function.
Pharmacogenomic assay oh both human and viral genomes may ultimately be used
to determine when therapy should be initiated ,which drugs ,and what doses.
New therapies are studied in order to free patient from a lifetime of drugs.
In Germany a man had been cured of HIV through a bone marrow transplant. The
donor was known to have two copies of a delta32 mutation in CCR5 gene, which
means that CD4+ can’t make a protein on their surface that HIV virus uses to
invade cells. The HIV-resistant cells took over the man’s immune system, ”curing”
him from HIV.(3)
Philp Gregory is studying in California a new gene therapy for HIV. He makes
artificial version of zinc finger nucleases(ZFN), which can distrupt any gene you
choose, in this case the CCR5 gene. Adding a harmless virus that encode for ZFN
in CD4+ cells taken from blood samples of 12 patient, the CCR5 genes are
sabotaged, and the modified CD4+ cells are re-injected into patients. The modified
cells replicate faster and live longer than the infected one, and become the
dominant CD4+.
Another gene therapy can be made with CD34 steam cells. Ronald Mitsuyasu
extracted CD34 from 74 people, and treated half of the cells with a placebo, and
the other half with a virus that carries a gene for a ribozyme, which, when
expressed, snips up the tat gene in any HIV that enters the cell, and stops its
replication. John Rossi is studying a third gene therapy, which uses three genes to
defend patient’s blood cells from HIV: one prevents production of CCR5,the other
two to sabotage HIV. He loaded the genes into CD34 stem cells and reinjected into
patients.

Conclusions
All physicians will soon need to understand the concept of genetic variability, its
interactions with the environment and implications for patient care. In fact the
practice of medicine has now entered an era in which the individual patient’s
genome will help determine the optimal approach to care it is preventive,
diagnostic or therapeutic.
Although the ART is still the best therapy for HIV, the various gene therapies and
the bone marrow transplant success show how in the future patient infected by HIV,
could be free from drugs.

BIBLIOGRAPHY

1)Gottlieb MS “ AIDS past and future” N Engl J Med 2001;344:1788-90

2)Simon V,Abdool Karim Quarrisha et al. “ HIV/AIDS
epidemiology,pathogenesis,prevention,and treatment.” Lancet 2006;368:489-504
3)Hutter Gero,Nowak D,Mossner M et al “Long-term control of HIV by CCR5
Delta32/delta32 atem cell transplantation” N Engl J Med 2009;360:692-8.
4)Andy Coghlan ” One shot to rid body of HIV”, NewScientist 2009 ;21:8-9