The T-cell response to HIV

Abstract

HIV is a disease in which the original clinical observations of severe opportunistic infections gave the first clues regarding the underlying pathology, namely that HIV is essentially an infection of the immune system. HIV infects and deletes CD4(+) T cells that normally coordinate the adaptive T- and B-cell response to defend against intracellular pathogens. The immune defect is immediate and profound: At the time of acute infection with an AIDS virus, typically more than half of the gut-associated CD4(+) T cells are depleted, leaving a damaged immune system to contend with a life-long infection.

Figure 1.

Evolution of the transmitted/founder virus in acute HIV-1 infection is largely driven by CD8⁺ T-cell responses. (A) The graph shows the falling viral load from the time of peak viremia, about 3 weeks after infection, to the establishment of the viral set point 160 days later. Virus taken at the first sampling (the time of screening or “day 0”) was characteristic of a single founder virus when sequenced; this is represented on the genetic map of the virus at the top right (B). At subsequent time points mutations appeared in all the viruses sequenced, shown by the bars on the genetic map to indicate the sites of the mutations. The bars are color coded to indicate rapid escape selected by CD8⁺ T cells, slower or late escape selected by CD8⁺ T cells, selection by neutralizing antibodies targeting the virus envelope, “reversions” from unusual sequences in the founder virus sequence to the sequence consensus in the whole database (the transmitted sequences may have been selected by CD8⁺ T cells in the transmitting sexual partner of the patient). At a few sites it was not clear what was selecting the amino acid change and these are shown in gray. (Adapted from McMichael et al. 2010; reprinted, with express permission, from the author.)

Figure 2.

Breadth of protein-specific CD8⁺ T-cell responses in relation to viral load. 578 persons infected with clade C virus were recruited, and comprehensive analysis of epitope targeting by PBMC was determined using a panel of overlapping peptides spanning all expressed viral proteins. Viral load of individuals in terms of the number of Gag (A)- and Env (B)-specific responses detected is shown, revealing that the broader the Gag-specific response, the lower the viral load, and the higher the Env-specific response, the higher the viral load, indicating that specificity impacts control. (Adapted from Kiepiela et al. 2007; reprinted, with permission, from Nature Publishers © 2007.)

Figure 3.

Three-dimensional ribbon representation of the HLA B protein, highlighting amino acid positions 62, 63, 67, 70, and 97 lining the peptide binding pocket that are significantly associated with HIV control. The peptide backbone of the epitope is also displayed. (Adapted from the International HIV Controllers Study 2010; reprinted, with permission, from Science © 2010.)