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  12th Conference on Retroviruses and Opportunistic Infections (CROI)
Feb 22-25, 2005
Boston, MA
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Innate Immunity: natural cellular mechanisms that battle HIV
  12th CROI Feb 2005
Reported for NATAP by David Margolis, MD
Univ of Texas, Southwestern Medical Center Dallas; VA Dallas; ACTG
Innate or non-adaptive immunity refers to immune responses that are non-specific, but able to recognize invading organisms as foreign. Innate antiviral immunity is ancient, and reflect eons of the struggle of multicellular organisms (like people) to survive. Evidence of the long battle of the mammalian cell to protect its genetic material from the onslaught of viral parasites is the existence of hundreds of endogenous retroviruses within the human genome, archaic viral sequences which no longer produce viruses but continue to be handed down from generation to generation. Exciting insights into several innate mechanisms by which human cells resist HIV infection and replication were made in the recent past, and were discussed at CROI. Obviously, the hope is that these mechanisms may be harnessed for the treatment of HIV infection.
APOBEC3G is a host cytidine deaminase. It acts on the HIV genome after it has been copied from RNA into DNA. Deoxycytidine (dC) within single stranded viral cDNA replication intermediates is deaminated by APOBEC3G to deoxyuridine (dU). APOBEC3G present in cells producing new viral particles is packaged into virions and transferred to the next round of target cells. In these target cells deamination occurs, causing G-to-A mutations (and less often C-to-T mutations) when the dU is copied on the next DNA strand. Thus, the packaging of APOBEC3G into progeny virions renders the virions defective, targeting them for a mutational death.
HIV has evolved the Vif protein to counteract the host defense effect of APOBEC3G. When Vif is present in sufficient quantity in virus-producing cells, APOBEC3G is no longer incorporated into virus particles. Vif accomplishes this, in part, by tagging APOBEC3G for destruction. A chemical modification of cellular proteins called ubiquitination is known to be a signal that targets proteins tagged in this way for degradation within the proteasome, the cell's garbage disposal organelle.
Chiu and co-workers from the Greene lab at UCSF (abstr. 30) presented evidence that APOBEC3G blocks viral replication by an additional mechanism. In resting cells, APOBEC3G is found in a small protein complex and blocks HIV replication. Surprisingly, this antiviral activity is something new and is distinct from the G-to-A editing function described above, as HIV DNA reverse transcripts found do not contain frequent G-to-A changes. When resting cells become activated, APOBEC3G is then found in a large protein complex and loses its antiviral activity. The group suggests that finding ways to keep APOBEC3G active and in the large protein complex might effectively block the growth of HIV entering cells.
Details of the mechanisms through which the HIV Vif protein targets APOBEC for degradation, thereby allowing HIV replication, were presented by Mehle and coworkers (abstr. 31). Vif targets APOBEC3G for proteasomal degradation by binding a complex of 3 human proteins called Cullin5, Elongin B, and Elongin C. The phosphorylation of a single amino acid (Ser 144) in Vif regulates this binding. Detailed understanding of the assembly and function of the complex that degrade APOBEC is likely to be important to formulating antiviral strategies aimed at blocking Vif or enhancing APOBEC function. Oddly, a Vif mutant that could not be phosphorylated at Ser 144 was defective in HIV replication but not in APOBEC3G degradation. This raised the possibility that Vif phosphorylation may also regulate another as yet unknown function important for HIV replication.
TRIM5a, a second pillar of innate antiviral immunity, was described in 2004 and discussed at CROI. There are nearly 40 genes of the TRIM family present in mouse and human. Although these proteins are likely to have multiple functions, blocking the growth of incoming viruses appears to be among them. Although the exact mechanism by which TRIM5a proteins inhibit retroviral replication is yet unknown, they block an early step of post-entry infection, likely uncoating of the incoming virus. This block to infection is species-specific. For example, HIV-1 enters the cells of Old World monkeys but the rhesus monkey version of TRIM5a blocks viral replication much more efficiently than by human TRIM5a. This is so despite the fact that human TRIM5a is 87% identical in amino acid sequence to the rhesus form. Stremlau and colleagues in the Sodroski lab (abstr. 34 and 174) showed that minimal amino acid changes in a critical region of TRIM called the spry domain affected which type of retroviruses were blocked by TRIM5a. This raised the possibilities that small molecules might be developed to enhance the capability of human TRIM5a _to block HIV replication.