HIV/AIDS

HIV World view Virus lifecycle Suface receptors Tropism Escape from CTL killing Drug resistance Role of APOBEC3G HIV vaccine strategies Reading: Parham Chapter 9

Global distribution of HIV infection

HIV structure

HIV is a simple virus with only 9 genes encoding 15 proteins. HIV is a retrovirus, with a 9.2 kilobase RNA genome that is copied into DNA by reverse transcriptase. The dsDNA copy is then inserted into the host genome.

Nothing is known about how HIV avoids NK mediated lysis Downregulation of MHC class I transcription ER retention Internalization from surface Downregulation of APOBEC G3 Binds uracil-DNA glycosylase (UNG)

Figure 9-15 part 1 of 4

Protease dependent maturation of HIV envelope

HIV infects cells that coexpress CD4 and either CCR5 or CXCR4 chemokine receptors. This leads to infection of either macrophages, which express low levels of CD4 and CCR5, or helper T cells, which express high levels of CD4 and CXCR4.

HIV evolves in the host from primary infections with M-tropic virus, to the AIDS inducing L-tropic form. L-tropic M-tropic

Some HIV infected people who are long term non-progressors to AIDS carry a recessive mutation in CCR5 10% frequency in some populations = ~1% mutant homozygotes

Figure 9-15 part 2 of 4

Red=RNA Blue=DNA Reverse transcriptase conversion of HIV RNA genome to double stranded DNA Reverse transcriptase has a high error rate, contributing to virus variability and escape mutants See next slide

dsDNA of HIV HIV integrase inserts reverse transcribed HIV DNA into host cell chromosome

Figure 9-15 part 3 of 4

Late gene expression generates structural proteins and the viral genome (unspliced) Early gene expression generates regulatory proteins

Figure 9-15 part 4 of 4

Figure 9-18

Figure 9-16

Figure 9-17

Figure 9-21

Figure 9-22

Mutated TCR contact residues HIV escape mutants that avoid cytotoxic T cell killing Mutations that affect processing of peptide to a size that can be held by MHC class I Mutated anchor residues Mutated TCR contact residues

Evidence for intense selection for mutational variants in patients 1 2 3 4 5 Sequence difference 6 7 8 9 time

Figure 9-19

Figure 9-20

Viral recombination can lead to fears about rapid acquisition of multidrug resistance

Sequence evidence that HIV may have jumped from chimpanzees to humans (and vice versa)

HIV-1 group M is believed to have arisen very recently

APOBEC3G is an AID related cytidine deaminase that suppresses viral disease by mutating single stranded DNA intermediates. HIV vif protein binds APOBECG3 and targets it for proteasomal degradation.

Ways that antibodies can suppress HIV

gp41 gp120

Evidence for intense selection for mutational variants in patients 1 2 3 4 5 Sequence difference 6 7 8 9 time

Vaccine generation Current vaccines issues include the problem of generating immunogens that include the trimeric form of gp120 to elicit neutralizing antibodies and strategies to get cytoplasmic expression to promote CTL priming. Because of the ability of HIV to undergo recombination, the use of attenuated HIV virus as vaccine has been abandoned for now. One promising approach is DNA vaccination, in which expression plasmids that drive expression of HIV protein subunits are introduced into host cells. So far, all attempts of generating HIV vaccines have failed.

Concepts HIV is a major public health problem Its high mutation rate combined with the ability to kill CD4 T cells accounts for its deadliness. CTL and antibodies probably keep the disease at bay and direct viral evolution. Virus countermeasures against the immune system include suppression of MHC class I, class II and CD4. Suppression of APOBEC3G, and probably other mechanisms. Development of a vaccine represents a major challenge.