Host factors dictate control of viral replication in two HIV-1 controller/chronic progressor transmission pairs

Abstract

Viremic controllers (VC) and elite controllers/suppressors (ES) maintain control over HIV-1 replication. Some studies suggested that control is a result of infection with a defective viral strain while others suggested host immune factors play a key role. Here we document two HIV-1 transmission pairs: one consisting of a patient with progressive disease and an individual who became an ES, and the second consisting of a patient with progressive disease and a VC. In contrast to another ES transmission pair, virus isolated from all patients was fully replication competent. These data suggests that some VC and ES are infected with HIV-1 isolates that replicate vigorously in vitro and are able to cause progressive disease in vivo. These data suggest that host factors play a dominant role in control of HIV-1 infection, thus it may be possible to control fully pathogenic HIV-1 isolates with therapeutic vaccination.

HIV-1 Reservoirs in Elite Controllers: Clues for Developing a Functional Cure?

“…Full-genome sequence analysis and phenotypic analyses have suggested that these isolates are fully pathogenic [4] and in a proof of concept study, virus cultured from ECs were shown to replicate vigorously and induce CD4 + T-cell depletion in humanized mice [7]. Transmission studies between patients with progressive disease (chronic progressors [CPs]) and ECs [8,9] have also suggested that some of these patients are infected with replication-competent virus and in one case, it appears that an EC transmitted virus to a CP [9]. Finally, some ECs develop virologic progression over time [10] and an EC was shown to develop viremia after chemotherapy [11].…”

Inhibitory Potential of Subpopulations of CD8+T Cells in HIV-1-Infected Elite Suppressors

“…CD8 ϩ T cells from ES maintain a polyfunctional response after stimulation with HIV-1 peptides (2,5,17), and there is significantly higher expression of granzyme B and perforin by HIV-1-specific CD8 ϩ T cells from ES than from CP (24,36,37). In addition, CD8 ϩ T cells from ES are much more effective at suppressing HIV-1 replication in autologous CD4 ϩ T cells in vitro than CD8 ϩ T cells from CP (3,7,13,37,48,49), and the inhibitory potential of CD8 ϩ T cells has recently been shown to be predictive of the rate of CD4 ϩ T cell decline early in viral infection (57). Current analysis of the CD8 ϩ T cell response in HIV-1 infection has focused primarily on unfractionated populations of CD8 ϩ T cells.…”

HLA-B*57 Elite Suppressor and Chronic Progressor HIV-1 Isolates Replicate Vigorously and Cause CD4 + T Cell Depletion in Humanized BLT Mice

“…While some studies have suggested that some ES are infected with attenuated or defective virus, others have shown that some ES are infected with replication-competent virus. We have documented the transmission of replication-competent HIV-1 isolates from CPs to ES (16,18), and studies have shown persistent viremia in ES (51-53), evolution of plasma virus over time (54)(55)(56), and a decrease in the frequency of latently infected CD4 ϩ T cells in ES treated with highly active ART (HAART) (57). However, other studies comparing individual viral proteins from ES and CPs have reported reduced fitness of ES Gag (10, 58), Env (59), reverse transcriptase (60), and Nef (61) proteins.…”

“…However, in other studies, replication-competent HIV-1 isolates were cultured from some ES (13)(14)(15), and full-genome sequence analysis of these replication-competent isolates did not reveal any large deletions or signature mutations (13). It has been very challenging to isolate virus from ES, and full-length genotypic analyses have been performed on replication-competent isolates obtained from fewer than 10 ES (11,13,(16)(17)(18) and just 3 HLA-B‫-75ء‬positive ES (13,16,18). Furthermore, studies comparing the growth kinetics of replication-competent virus from ES to those of multiple isolates from patients with progressive disease have not been performed.…”

“…We were not able to isolate replication-competent virus from 6 other ES. Isolates from one ES (ES 38) have been previously described (18). RNA was isolated from positive-well supernatants.…”