Human Immunodeficiency Virus (HIV) is the causative agent of AIDS. It is a retrovirus belonging to the lentivirinae family. HIV reverse-transcribes its RNA to DNA and then back to RNA.
Leeches and mosquitoes are unable to transmit HIV because the virion is unable to replicate outside of a warm mammalian host. Due to HIV's specific temperature and environment requirements, it is transferred between mammals.
Cellular requirements for productive HIV-1 replication:
CD4 surface molecule
CCR5 - the majority of new infections are by viruses that utilize this co-receptor; regardless of the mode of transmission.
CXCR4 -- approx. 50% of individuals will have viruses that switch to using this co-receptor. Associated with faster disease progression.
Activated Cell: Cell must progress past the G1b phase of the cell cycle
Reverse Transcriptase (RT): Encoded by the pol gene, it does not have a proofreading function. As a result, it si very error prone. There is approximately one error "mutation" per round of replication.
Implications of RT error: Approximately one error is made per replication cycle. With up to 1x109 viral particles made per day, it is speculated that every possible mutation is present. As a result, there is tremendous potential for generation of drug resistance. Mutations also allow HIV to escape from immune recognition. Mutations can confer a fitness advantage, be deleterious or make no difference at all to the viral fitness. Areas critical for viral function are conserved, although there is tolerance for variability in areas not as critical and especially those recognized by the immune system.
There is innate and adaptive immunity. Adaptive immunity involves two major types of cells:
So Why Don't CD8+ T-cells Completely Control HIV?
Loss of CD4+ T-cells compromises the ability of CTL to work.
HIV mutation abolishes recognition of HIV by CTL.
How do CTL recognize HIV or other antigens?
The T-cell receptor on CTL bind short antigen-derived peptides (9-10 amino acids).
These peptides are presented by proteins on the surface of the cells called Human Leukocyte Antigens (HLA). These are the same proteins that make up your "tissue type".
Human Leukocyte Antigens:
Are encoded by the major histocompatibility complex (MHC) on chromosome 6 in humans.
Class I antigens are found on all nucleated cells. CD8+ T cells recognize Class I antigens.
Class II antigens are 1Â° on antigen Presenting cells (macrophages, dendritic cells and B cells). = DR, DP, DQ
CD4+ T cells recognize Class II antigens.
Viral set-point is indicative of the rate of disease progression. The higher the viral load, the faster the disease progression. It peaks, lowers, plateaus, then increases before terminating.
Long-Term NonProgressors (LTNP)
~ 1% of HIV infected individuals
Infected >10 years, CD4+ T-cells > 500/Î¼l of blood, < 5 X 103 copies of viral RNA/ml of blood, no clinical disease despite remaining untreated.
Viral factors: attenuated virus e.g. Nef deletions
Associated with HLA-B*57, HLA-B*27
HLA Association with LTNP
Depending on the cohort, HLA-B*57 individuals make up to 85% of LTNP.
The association with Class I suggests that CTL responses are involved.
However, HLA can't be the only factor.
HLA-B*57 individuals are present among cohorts of â€œprogressorsâ€ in the same frequency as the general population.
HLA-B*57 homozygosity does not necessarily confer LTNP status.
So why is HLA-B*57 so strongly associated with LTNP status?
HLA-B*57 LTNP Target Conserved Regions Of HIV-1 Derived Proteins
Does this confer better protection from disease progression?
Migueles et al.* have shown that HLA-B*57 progressors also recognize conserved regions of HIV-1 derived proteins. These experiments were all done years after the initial infection.
Is Timing Everything?
The viral set-point is an indicator of the rate of disease progression. The viral set-point is reached early after infection. Shouldn't we be looking at immune responses early in infection? If LTNP are defined as not progressing to disease progression >10 years, how do you know who to study?
Multi-Center AIDS Cohort Study (MACS)
A cohort of HIV-infected men and at-risk men. Take epidemiological data and biological samples every six months for 20 years. Have individuals who seroconverted while under study. Have HLA-typed many of the men.
Questions We Are Addressing:
Do CTL from LTNP target conserved regions within HIV earlier than Progressors?
Early in infection, do CTL from LTNP target more conserved regions than Progressors?
Is it multi-factorial? For example: maybe CTL all from HLA-B*57 target a high number of conserved regions, but LTNP have other responses that tip the balance in favor of the immune response? Antibodies? Innate immunity?
There was no significant difference in the viral load between LTNP and Progressors at the first time-point post-infection. Oddly enough, while both CTL from LTNP and Progressors targeted conserved epitopes, overall, LTNP targeted more non-conserved epitopes than Progressors. Does this help?? During early HIV-1 infection 3/7 LTNP had CTL responses to Env compared to 0/7 progressors.
6/7 LTNP vs. 1/7 Progressors targeted an epitope in p24 (capsid).
The 1 LTNP that did not target this epitope at the earliest time-point, targeted it soon afterwards. He retains that response today, 20 years post-infection. He also still responds to the same epitope in Env as he did 20 years ago.
To measure responses, we are using peptides that represent the consensus sequences for HIV-1 clade B.
Even though we have measured CD8+ T-cell responses early in infection, 3 to 9 months post-infection is a long time! Within weeks many other viral infections, like influenza, are won or lost.