Infrequent Recovery of HIV from but Robust Exogenous Infection of Activated CD4⁺T Cells in HIV Elite Controllers

Abstract

HIV elite controllers are able to control HIV-1 infection spontaneously to undetectable levels in the absence of antiretroviral therapy, but the mechanisms leading to this phenotype are poorly understood. Although, low frequencies of HIV infected peripheral CD4+ T-cells have been reported in this group, it remains unclear to what extent this is due to viral attenuation, active immune containment, or intracellular host factors that restrict virus replication. Here we assessed proviral DNA levels, autologous viral growth from and infectability of in-vitro activated, CD8+ T-cell depleted CD4+ T cells from HIV elite controllers (mean VL<50cp/ml), viremic controllers (mean VL<2000cp/ml), chronic progressors and HAART treated individuals. Although we successfully detected autologous virus production in ex-vivo activated CD4+ T-cells from all chronic progressors and most of the viremic controllers we were only able to measure robust autologous viral replication in only 2 of 14 elite controllers subjected to the same protocol. In vitro activated autologous CD4+ T-cells from elite controllers, however, supported infection with both X4 and R5 tropic HIV strains at comparable levels to CD4+ T-cells from HIV negative subjects. Proviral DNA levels were the lowest in elite controllers, suggesting that extremely low frequencies of infected cells contributes to difficulty in isolation of virus. These data indicate that elite control is not due to inability of activated CD4+ T-cells to support HIV infection, but the relative contribution of host and viral factors that account for maintenance of low level infection remain to be determined.

CD4+ T cells from elite controllers resist HIV-1 infection by selective upregulation of p21

“…Several prior studies have demonstrated that CD4 + T cells from elite controllers are generally permissive to HIV-1 infection and that they can harbor pathogenic, replication-competent virus in vivo (12)(13)(14). Moreover, after in vitro activation, CD4 + T cells from elite controllers are capable of supporting productive HIV-1 infection (13,15), but prior experimental procedures, particularly when involving vigorous in vitro activation of cells, may have been insufficiently sensitive to detect intrinsic resistance mechanisms that restrict HIV-1 replication by altered expression patterns of host genes.…”

CD4+T cells from elite suppressors are more susceptible to HIV-1 but produce fewer virions than cells from chronic progressors

“…One study suggested that cells from ES were resistant to infection because of selective up-regulation of cyclin-dependent kinase inhibitor p21 (31), whereas another study also found resistance of ES CD4 + T cells to HIV-1 infection but showed that p21 plays no role in this phenomenon (32). A third study found that CD4 + T cells from ES were as susceptible to infection as CD4 + T cells from HIV-1 seronegative donors (9). Because activation by either method, PHA or anti-CD3 antibodies, has been shown to modulate coreceptor density, which, in turn, affects susceptibility to infection (33)(34)(35), we have studied the susceptibility of unstimulated CD4 + T cells.…”

Circulating Monocytes Are Not a Major Reservoir of HIV-1 in Elite Suppressors

“…Quantitative PCR (qPCR) was performed using long terminal repeat (LTR) primers to determine the frequency of proviral HIV-1 DNA in circulating CD4 ϩ T cells and monocytes. Single-step qPCR was performed on each sample under previously published conditions (29). The proviral HIV-1 DNA copy number was calculated relative to the RNase P gene copy number (Applied Biosystems), which had been previously quantified with a standard curve.…”