Demographic Processes Affect HIV-1 Evolution in Primary Infection before the Onset of Selective Processes

Abstract

HIV-1 transmission and viral evolution in the first year of infection were studied in 11 individuals representing four transmitter-recipient pairs and three independent seroconverters. Nine of these individuals were enrolled during acute infection; all were men who have sex with men (MSM) infected with HIV-1 subtype B. A total of 475 nearly full-length HIV-1 genome sequences were generated, representing on average 10 genomes per specimen at 2 to 12 visits over the first year of infection. Single founding variants with nearly homogeneous viral populations were detected in eight of the nine individuals who were enrolled during acute HIV-1 infection. Restriction to a single founder variant was not due to a lack of diversity in the transmitter as homogeneous populations were found in recipients from transmitters with chronic infection. Mutational patterns indicative of rapid viral population growth dominated during the first 5 weeks of infection and included a slight contraction of viral genetic diversity over the first 20 to 40 days. Subsequently, selection dominated, most markedly in env and nef. Mutants were detected in the first week and became consensus as early as day 21 after the onset of symptoms of primary HIV infection. We found multiple indications of cytotoxic T lymphocyte (CTL) escape mutations while reversions appeared limited. Putative escape mutations were often rapidly replaced with mutually exclusive mutations nearby, indicating the existence of a maturational escape process, possibly in adaptation to viral fitness constraints or to immune responses against new variants. We showed that establishment of HIV-1 infection is likely due to a biological mechanism that restricts transmission rather than to early adaptive evolution during acute infection. Furthermore, the diversity of HIV strains coupled with complex and individual-specific patterns of CTL escape did not reveal shared sequence characteristics of acute infection that could be harnessed for vaccine design.

Tracking the Emergence of Host-Specific Simian Immunodeficiency Virus env and nef Populations Reveals nef Early Adaptation and Convergent Evolution in Brain of Naturally Progressing Rhesus Macaques

“…This observation, coupled with the finding that the proportion of nef codons under negative selection was highest in plasma samples from the same macaques suggests the hypothesis that the emergence of viral strains capable of efficiently invading the CNS may require the fixation of functional Nef capable of altering the macrophage migratory mode. The fixation of nef could also be due to a biological mechanism, such as an early HLA-restricted CTL response, rather than early adaptive viral evolution (64). Further examination of the signatures identified in this study could yield information important for vaccine or therapeutic programs targeting nef.…”

Transmitted/Founder HIV-1 Subtype C Viruses Show Distinctive Signature Patterns in Vif, Vpr, and Vpu That Are Under Subsequent Immune Pressure During Early Infection

“…25,36 Vif and Vpr, but not Vpu, have low entropy in t/f viruses To investigate HIV-1C Vif, Vpr, and Vpr amino acid diversity, we reconstructed each patient's t/f virus, using the consensus sequence from the earliest time point postinfection, and computed Shannon entropy scores across Vif, Vpr, and Vpu t/f alignments. The median number of sequences per patient used for reconstruction was 10 [interquartile range [(IQR): [5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23][24]. The reconstructed t/f viruses exhibited relatively low interpatient amino acid entropy in Vif (median 0.00; IQR: 0.00-0.22) and Vpr (median 0.00; IQR: 0.00-0.22) (Fig.…”

“…Following this, cytotoxic T lymphocytes (CTLs) play a critical role in the control of HIV infection and mediate another bottleneck event from which escape variants emerge. 11 Human leukocyte antigen (HLA) class I-mediated CTL responses are important predictors of disease progression 12 that drive virus escape mutations that are highly adapted to the host environment. 4,[13][14][15][16][17][18] Recent studies employing ultradeep sequencing 3,19 confirmed dramatic shifts in the frequencies of epitope variants during the first weeks of HIV infection.…”

Fitness-Balanced Escape Determines Resolution of Dynamic Founder Virus Escape Processes in HIV-1 Infection

“…However, in many responses detected during primary HIV-1 infection, clear evidence of reversions is difficult to determine and escape pathways are less consistent (5,11,30). Interestingly, frequent sampling of viral populations during acute infection revealed that escape processes can be highly dynamic, with multiple simultaneous or rapidly sequential and mutually exclusive escape mutations arising within a targeted epitope (5). It is unclear which selective forces promote these dynamic escape processes and why some variants are selected over others.…”

“…These responses consistently promote dominant escape and reversion pathways in which only a select few mutations are required (27)(28)(29). However, in many responses detected during primary HIV-1 infection, clear evidence of reversions is difficult to determine and escape pathways are less consistent (5,11,30). Interestingly, frequent sampling of viral populations during acute infection revealed that escape processes can be highly dynamic, with multiple simultaneous or rapidly sequential and mutually exclusive escape mutations arising within a targeted epitope (5).…”