Evolution of proviral gp120 over the first year of HIV-1 subtype C infection

Abstract

The evolution of proviral gp120 during the first year after seroconversion in HIV-1 subtype C infection was addressed in a case series of eight subjects. Multiple viral variants were found in two out of eight cases. Slow rate of viral RNA decline and high early viral RNA set point were associated with a higher level of proviral diversity from 0 to 200 days after seroconversion. Proviral divergence from MRCA over the same period also differed between subjects with slow and fast decline of viral RNA, suggesting that evolution of proviral gp120 early in infection may be linked to the level of viral RNA replication. Changes in the length of variable loops were minimal, and length reduction was more common than length increase. Potential N-linked glycosylation sites ranged ±one site, showing common fluctuations in the V4 and V5 loops. These results highlight the role of proviral gp120 diversity and diversification in the pathogenesis of acute HIV-1 subtype C infection.

Importance of Viral Sequence Length and Number of Variable and Informative Sites in Analysis of HIV Clustering

“…These subgenomic regions included (1) a partial pol sequence spanning the region encoding HIV-1 protease and the first 335 amino acids of reverse transcriptase, which corresponds to the sequence produced by ViroSeq, [38][39][40][41] nt positions 2,253-3,554; (2) partial env sequences spanning the region encoding the gp120 V1C5 region, [42][43][44] nt positions 6,570-7,757; (3) ''product 2'' spanning the 3¢-end of gag and almost the entire pol, 45 nt positions 1,486-5,058; and (4) ''product 4'' spanning vpu, env, nef, and TATA-box in the U3 region of 3¢-LTR, 45 nt positions 5,967-9,517. In addition, combinations of the targeted subregions included gag + pol, gag + env, pol + env, gag + pol + env, and product 2 + product 4.…”

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

“…Patients were enrolled in an HIV-1C primary infection cohort in Botswana, 21,22 and a subset of 17 subjects was selected based on the stage of HIV infection: six acutely infected individuals (patient code A to H) and 11 randomly selected early infections (patient code OC to QR) ( Table 1). Acutely infected individuals were identified before seroconversion by a positive HIV-1 reverse transcription polymerase chain reaction test accompanied by negative HIV-1 serology (Fiebig stage II).…”

“…The time of seroconversion (Day 0) was estimated as the midpoint between the last seronegative test and the first seropositive test for the acutely infected subjects and by midpoint of the corresponding Fiebig stage for the recently infected subjects. 21 Written informed consent was obtained from all study participants, and ethics approval for this research was obtained from the Human Research Development Committee of the Botswana Ministry of Health and the Office of Human Research Administration at the Harvard School of Public Health.…”

“…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.…”

“…All available subtype C sequences fitting these criteria were included in our analysis. The majority of sequences included (14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27) South Africa (*50%), followed by Botswana (*25%) and others (Supplementary Table S1; Supplementary Data are available online at www.liebertpub.com/aid). A maximum likelihood phylogeny inferred from our combined early and chronic HIV-1 vif sequences was created to confirm that the acute/early sequences are generally interspersed among the chronic ones ( Supplementary Fig.…”