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

  1. B. Julg1,
  2. F. Pereyra1,
  3. M. J. Buzón3,
  4. A. Piechocka-Trocha1,2,
  5. M. J. Clark1,
  6. B. M. Baker1,
  7. J. Lian1,
  8. T. Miura1,2,5,
  9. J. Martinez-Picado3,4,
  10. M. M. Addo1, and
  11. B. D. Walker1,2
  1. 1Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology and Harvard, Boston, Massachusetts
  2. 2Howard Hughes Medical Institute, Chevy Chase, Maryland
  3. 3irsiCaixa Foundation, Hospital Universitari Germans Trias i Pujol, Badalona, Spain
  4. 4Institució Catalana de Recerca i Estudis Avançats, Barcelona, Spain
  5. 5Institute of Medical Science, University of Tokyo, Tokyo, Japan
  1. Reprints or correspondence: Dr Bruce D. Walker, Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology and Harvard University, 149 Thirteenth St, Charlestown, MA 02129 (bwalker{at}partners.org).
 
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Abstract

Background. Human immunodeficiency virus (HIV) elite controllers are able to control infection with HIV-1 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 these are due to viral attenuation, active immune containment, or intracellular host factors that restrict virus replication.

Methods. 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 viral load, <50 copies/mL), viremic controllers (mean viral load, <2000 copies/mL), chronic progressors, and individuals receiving highly active antiretroviral therapy.

Results. Although we successfully detected autologous virus production in ex vivo activated CD4+ T cells from all chronic progressors and from most of the viremic controllers, we were 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 those in CD4+ T cells from HIV-uninfected subjects. Proviral DNA levels were the lowest in elite controllers, suggesting that extremely low frequencies of infected cells contribute to difficulty in isolation of virus.

Conclusions. These data indicate that elite control is not due to inability of activated CD4+ T cells to support HIV infection, but the relative contributions of host and viral factors that account for maintenance of low-level infection remain to be determined.

A small proportion of human immunodeficiency virus type 1 (HIV-1)—infected individuals, called elite and viremic controllers, spontaneously control plasma HIV RNA levels to undetectable (elite controller) or <2000 copies/mL (viremic controller) in the absence of antiretroviral therapy. Some have postulated that elite controllers exhibit control predominantly as a consequence of infection with replication-defective virus, resulting in poor viral outgrowth [1–3]. Although impaired in vitro viral replication capacity has been documented in some elite controllers [4], studies thus far have shown that replication-competent viruses can be isolated from these individuals as well, suggesting that not all elite controllers are infected with defective viruses [5, 6]. Host genetic analyses suggest that immune mechanisms, associated with the major-histocompatibility complex, contribute to the extraordinary control of viral replication observed in this unique patient population [7–12]. The overrepresentation of certain HLA class I alleles [10, 13], CD8+ T cell—depletion studies [14], evidence of selection for cytotoxic T lymphocyte epitope mutations [12, 15], and in vitro studies showing strong antiviral activity of CD8+ T cells [11, 16] suggest that cellular immune mechanisms are involved in this remarkable antiviral control.

Interestingly, long-term nonprogressors not only exhibit reduced levels of plasma viral replication but also have lower numbers of CD4+ T cells with integrated HIV provirus, compared with individuals with fast-progressive disease and AIDS [17, 18]. This finding suggests that (a) these individuals have a unique capacity to control viral replication actively over time, (b) they are infected with viruses that do not replicate, and/or (c) these individuals possess CD4+ T cells with a unique ability to resist HIV infection. To begin to explore the 2 latter possibilities, we sought to determine whether elite controllers are infected with replication-competent virus, compared with a group of normal HIV-infected progressors, and whether their CD4+ T cells, after vigorous in vitro activation, are differentially susceptible to HIV-1 infection in vitro, compared with those of seronegative control subjects.

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Materials and Methods

Study subjects. A total of 25 HIV elite controllers with plasma HIV RNA levels <50 copies/mL were randomly selected from the International HIV Controllers Study. Also included were 10 viremic controllers with plasma HIV RNA levels of 50–2000 copies/mL (mean plasma HIV RNA, 1256 copies/mL). Both groups were antiretroviral therapy naive, and a minimum of 3 qualifying determinations of plasma HIV RNA levels spanning at least a 12-month period was required for inclusion in the study. Eleven untreated viremic progressors with plasma HIV RNA levels >10,000 copies/mL (mean plasma HIV RNA, 125.158 copies/mL) and 9 subjects receiving successful highly active antiretroviral therapy (HAART) (mean plasma HIV RNA, <75 copies/mL) were recruited from outpatient clinics at local Boston hospitals. HAART was defined as treatment with ⩾3 antiretroviral drugs, including 2 nucleoside reversetranscriptase inhibitors and a nonnucleoside reverse-transcriptase inhibitor or a protease inhibitor. Additionally, we obtained blood from 12 healthy control subjects. All subjects gave written informed consent.

Assessment of autologous virus production. To detect autologous virus growth, CD4+ cells were purified from freshly isolated peripheral blood mononuclear cells (PBMCs) by negative selection using the Rosette Sep CD4+ cell enrichment cocktail (Stemcell Technologies) depleting CD8+ T cells, natural killer cells, B cells, macrophages, monocytes, and dendritic cells. CD4+ cells were then stimulated in interleukin 2 (50 units/mL) containing T cell medium in the presence of a bispecific anti-CD3:anti-CD8 monoclonal antibody, which selectively activates CD4+ T lymphocytes while simultaneously depleting all remaining CD8+ T cells [19]. CD4+ T cell blasts, generated from HIV-uninfected donors, were added every 7 days to maintain the cultures and to provide additional targets for viral outgrowth.

In parallel, an aliquot of CD4+ T cells from elite controllers was infected with a clinical HIV-1 (X4) isolate at multiplicity of infection of 0.01 as described previously [20] and was maintained under the same culture conditions. Every 2–3 days, p24 was measured in culture supernatants using a p24-based enzyme- linked immunosorbent assay (ELISA; PerkinElmer Life Sciences) in accordance with the manufacturer's protocol.

Infectability assays. To determine in vitro infectability of CD4+ T cells and their intrinsic ability to support viral replication, comparing elite controllers with HIV-uninfected individuals, whole PBMCs were depleted from CD8+ T cells using anti-CD8 magnetic beads (DYNAL) in accordance with the manufacturer's protocol, and CD4+ T cell blasts were generated using the bispecific anti-CD3:anti-CD8 antibody in the presence of interleukin 2 (50 units/mL) for 3 days. CD4+ T cells were then infected with X4 and R5 HIV laboratory strains (NL4-3 and JRCSF) at a multiplicity of infection of 0.01 for 4 h. Cells were washed and then cultured in interleukin 2 (50 units/mL) containing medium for 7 days without the addition of further CD4 blasts, and p24 was measured in culture supernatants every 2–3 days.

Real-time PCR-based quantification of proviral HIV-1 DNA. HIV-1 DNA purification from 107 PBMCs was performed with a standard protocol (QIAamp DNA Blood Kit; Qiagen). A single-step real-time polymerase chain reaction (PCR) was used to quantify proviral HIV-1 DNA in a 50-µL PCR reaction mix containing 25 µL of TaqMan Universal PCR Master Mix (Applied Biosystems), 20 µL of HIV-1 DNA, and primers and probe that anneal to the 5′ and 3′ ends of the R and U5 region of the long terminal repeat (LTR), respectively, as has been described previously [21], using forward primer 5′-GG CTA ACT AGG GAA CCC ACT G-3′ and reverse primer 5′-GCT AGA GAT TTT CCA CAC TGA CTA A-3′. The fluorescence TaqMan probe was 5′-GGA TCT CTA GTT ACC AGA GTC A-3′. Amplification reactions were performed with an Applied Biosystems 7000 real-time PCR system. The thermocycling conditions were 95°C for 10 min, 50 cycles at 95°C for 15 s and 60°C for 1 min, and a final cycle at 72°C for 5 min. Copy-number estimation of proviral HIV-1 DNA was performed in duplicate and was determined by extrapolation from a standard curve generated with a plasmid that harbors the sequence of the HIV-1 LTR and CCR5 gene. Proviral HIV-1 DNA copy number was calculated relative to CCR5 gene copy number previously quantified with the standard curve.

HLA typing. HLA class I typing was performed as described previously [22].

Statistical analyses. Values throughout the text are expressed as mean ± standard deviation. P values were calculated using the Kruskal-Wallis test followed by Dunn's method for multiple comparisons and Wilcoxon rank-sum tests for pairwise comparisons.

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Results

Autologous virus production. We first evaluated whether ex vivo activation of CD4+ T cells from elite controllers and viremic controllers resulted in outgrowth of autologous virus, comparing these results with those obtained from chronically HIV-infected patient subpopulations. PBMCs were stimulated with a bispecific monoclonal antibody that results in the selective expansion of CD4+ T cells and the elimination of CD8+ T cells [19], and uninfected activated donor CD4+ cells were added to the cultures weekly, such that viral outgrowth was being examined in non-autologous cells. Of 14 elite controllers examined, virus was detected in vitro in only 3, and in 1 subject, detection by p24 ELISA was transient and could not be confirmed by repeated real-time PCR. In contrast, 9 of 9 untreated HIV progressors and 3 of 4 HAART-treated subjects demonstrated p24 antigen production in the stimulated cultures (Figure 1A). Although virus was significantly less frequently detected in the elite controllers, in both of the individuals in whom sustained virus production was observed, log10 p24 levels of 4.08–4.82 log10 pg/mL could be detected, comparable to the p24 antigen levels observed in HIV progressor cultures (3.91 ± 0.5 log10 pg/mL), suggesting that the viruses that did grow were as replication competent as were the viruses infecting the progressors (Figure 1B). Viral replication was not detectable in CD4+ cultures from the remaining 11 elite controllers, despite that these cultures were maintained for a median of 37 ± 12 days and some for as long as 78 days. Interestingly, 8 of 10 HIV viremic controllers displayed robust viral replication in vitro after 20 days despite their low plasma HIV RNA loads in vivo, with levels lower but comparable to those observed in progressors (log10 p24 levels, log10 3.4 ± 1.3 pg/mL in viremic controllers and log10 3.91 ± 0.5 pg/mL in progressors) (Figure 1B). Of the remaining 2 viremic controllers, one showed a delayed viral growth (first virus detected after >30 days), whereas no autologous virus was detected in the other subject's cultures for up to 50 days. Interestingly, both individuals were homozygous for protective HLA B alleles (B2705/B5701 and B5701/B5703, respectively), which suggests that a strong immune response may have led to the reduced viral reservoir in these individuals, suggesting the possible role of active immune containment of viral replication (Figure 1B). These data indicate furthermore that replication-competent HIV can be isolated from a minority of elite controllers, suggesting either that the majority of elite controllers are infected with replication-defective virus or that the frequency of HIV-1-infected CD4+ T cells is extremely low in the peripheral blood of elite controllers, resulting in a reduced chance of capturing an infected cell in a given PBMC sample.

Figure 1
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Figure 1

Autologous virus replication in activated autologous CD4+ T cells. A, Kinetics of autologous virus replication (log10 p24 levels in pg/mL) among elite controllers (EC), viremic controllers (VC), chronic progressors, and individuals receiving highly active antiretroviral therapy (HAART). B, Mean log10 p24 levels (in pg/mL) after 10 days (filled symbols) and 20 days (open symbols) among EC, VC (§, HLA B5701/B5703; #, HLA B2705/B5701), chronic progressors, and individuals receiving HAART.

Proviral HIV-1 DNA. To test the hypothesis that the reduced outgrowth of autologous virus from in vitro activated HIV controller CD4+ T cells is the result of the low frequency of infected CD4+ cells in the peripheral blood, we measured HIV proviral DNA levels in total PBMCs of 7 elite controllers and 5 viremic controllers and compared these with the levels of 5 chronic progressor patients and 6 virally suppressed individuals receiving HAART. Elite controllers showed significantly lower levels of provirus, compared with viremic controllers and chronic progressors (12.79 ± 20.92 proviral DNA copies/106 PBMCs for elite controllers vs. 94.80 ± 95.47 proviral DNA copies/106 PBMCs for viremic controllers and 792.0 ± 1383 proviral DNA copies/106 PBMCs for chronic progressors; P < .05 and P < .001, respectively). In contrast, we did not detect any significant difference between elite controllers and patients receiving HAART (34.76 ± 32.74 proviral DNA copies/106 PBMCs; not significant) (Figure 2). This observation suggests that the low viral reservoir in the elite controller CD4+ compartment, rather than general replication incompetence of their infecting virus, might lead to limited outgrowth of autologous virus in the elite controller. This assumption is supported by the observation that the elite controller who demonstrated the strongest outgrowth of autologous virus in the long-term cultures (peak log10 p24 levels, 4.82 log10 pg/mL at day 28) showed the highest proviral DNA loads of the elite controller group (58.33 proviral DNA copies/106 PBMCs).

Figure 2
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Figure 2

Proviral loads (DNA copies/106 peripheral blood mononuclear cells [PBMCs]) among elite controllers (EC), viremic controllers (VC), chronic progressors, and individuals receiving highly active antiretroviral therapy (HAART). n.s., not significant.

Susceptibility to HIV infection. The reduced outgrowth of autologous virus from in vitro activated CD4+ T cells in elite controllers could also indicate that these cells may be less permissive to HIV virus replication. To test this hypothesis, we determined whether the same elite controller CD4+ T cells used for the outgrowth cultures were susceptible to in vitro infection with an X4 tropic HIV-1 clinical isolate (F716). We therefore infected CD4+ T cells with exogenous virus in parallel while setting up the outgrowth cultures. CD4+ T cells from all elite controllers were readily infectable and exhibited peak log10 p24 levels of log10 4.29 ± 0.3 pg/mL after 10 days (Figure 3). We next ascertained whether there were differences in the level of superinfecting viral production in in vitro stimulated CD4+ T cells between elite controllers and non-elite controller control subjects. Because of the confounding issue of the outgrowth of autologous virus in cells from viremic individuals, we compared CD4+ T cell infectability of elite controllers with that of a group of matched HIV-seronegative controls. By infecting with X4 and R5 tropic (NL4-3 and JRCSF) HIV-1 strains, we were able to observe peak levels of viral replication in CD4+ T cells from elite controllers on day 7, reaching a mean log10 p24 level of log10 4.98 ± 0.45 pg/mL for NL4-3 infection and 5.28 ± 0.49 pg/mL for JRCSF infection (Figure 4A and 4B). Similar levels and kinetics of viral replication were seen in CD4+ cell cultures from HIV-uninfected individuals (log10 p24 level, log10 4.88 ± 0.59 pg/mL for NL4-3 infection and log10 5.26 ± 0.42 pg/mL for JRCSF infection, respectively). These data suggest that CD4+ T cells from elite controllers, after exogenous activation, are not resistant to HIV-1 in vitro infection.

Figure 3
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Figure 3

Replication of a human immunodeficiency virus type 1 clinical isolate in activated CD4+ T cells of 14 elite controllers.

Figure 4
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Figure 4

Replication of the X4 tropic human immunodeficiency virus type 1 (HIV-1) strain NL4-3 (A) and the R5 tropic HIV-1 strain JRCSF (B) in activated CD4+ T cells of 12 elite controllers and 12 HIV-uninfected (HIV—) individuals (multiplicity of infection, 0.01). Shown are mean log10 p24 levels (in pg/mL) at day 7.

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Discussion

In this study, we investigated whether low plasma HIV RNA levels in elite and viremic controllers are associated with infection by replication-incompetent viruses or whether their CD4+ T cells are not able to produce virus or become infected. To address these possibilities, purified CD4+ T cells from elite controllers and viremic controllers were isolated and were stimulated in vitro, and outgrowth of autologous virus was assessed. Among 14 elite controllers tested, autologous virus grew robustly from samples derived from only 2 individuals' CD4+ T cell cultures. In contrast, in vitro activated CD4+ T cells from all elite controllers were readily infectable with exogenous virus following in vitro stimulation, suggesting that the elite control observed is not associated with an inability of activated CD4+ cells to support HIV replication. However, we cannot exclude that a distinct interaction between elite controller CD4+ T cells and their infecting viral strain might exist that would not allow viral outgrowth in these individuals. Because of the limitation in retrieving viral strains from elite controllers, we were unable to test this hypothesis.

Our results are consistent with those of recent reports, in which difficulty in growing autologous virus was observed in the vast majority of elite controllers [5, 6]. However, because all elite controller CD4+ T cells were infectable and produced large quantities of virus after superinfection with laboratory or primary HIV strains, our data suggest that low levels of virally infected cells in the peripheral circulation, rather than an intrinsic inability of their activated CD4+ T cells to support robust virus replication, may explain the difficulty in isolating autologous virus in vitro. This was supported by the reduced levels of HIV proviral DNA we found in the elite controllers, compared with those in chronic progressors and even viremic controllers or individuals receiving suppressive antiretroviral therapy. Consistent with this observation, we detected the strongest outgrowth of autologous virus in the elite controller with the highest proviral DNA levels.

Since autologous virus replicated readily in most of the viremic controllers despite their low plasma viral loads, the exclusive explanation of HIV control by a defective infecting virus is questionable. Ours and other groups have shown that elite control is associated with persistent low but fluctuating levels of viremia, suggesting individual differences in host immune responses [23, 24]. Our observation that the 2 viremic controllers who showed either a delayed or no autologous viral outgrowth express the protective HLA B alleles B27 and B57 implies that the reduction of the viral reservoir in the peripheral CD4+ compartment may be mediated by a potent and persistent immune response. These findings are supported by a recent report from Saez-Cirion et al [25], who demonstrated that, among elite controllers with weak antiviral CD8+ T cell responses, highly in vitro replicative viruses were detectable.

It has been postulated that CD4+ T cells from elite controllers may be less susceptible to infection, as has been shown for individuals who are highly exposed to HIV-1 and yet remain uninfected [26, 27]. However, detectable low level viremia in the majority of elite controllers [24] points to a small persistent cellular reservoir for ongoing viral replication. Here, we artificially activated CD4+ T cells from all donors, and after maximal activation, superinfected the cells with either an X4 or an R5 laboratory strain. In this setting, we did not observe any differences among the elite controllers or HIV-uninfected control subjects in their ability to support viral replication. This observation argues against but does not disprove the hypothesis that host factors may render activated CD4+ T cells less infectable as a cause for the reduced frequencies of infected peripheral CD4+ T cells in HIV controllers. However, it is still plausible that other factors, such as potential in vivo differences in CD4+ T cell activation levels or more subtle differences in the ability to support autologous virus replication, may differentiate the infectability of CD4+ cells of elite controllers, compared with those of other individuals. This said, it is still plausible that added intrinsic differences in activation potentials among CD4+ T cells from elite controllers and controls may account for differences in susceptibility to HIV-1 infection or in the burst size of viruses produced per infected cell.

Overall, these data suggest that in vitro activated CD4+ cells from elite controllers can readily accommodate HIV replication and that elite controllers can harbor replication-competent HIV. The poor autologous virus outgrowth from elite controllers is likely related to the low frequency of HIV-infected cells in the peripheral circulation of elite controllers. Low levels of HIV-infected CD4+ T cells in vivo are likely due to highly antiviral immune pressure unique to HIV controllers, but further studies examining subtle differences in innate effector mechanisms that might be detectable with more sensitive assays are warranted.

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Acknowledgments

Financial support. National Institutes of Health (RO1 AI030914 to B.D.W.), Bill and Melinda Gates Foundation, and Centers for AIDS Research.

Potential conflicts of interest. All authors: no conflicts.

  • Received December 22, 2009.
  • Accepted February 24, 2010.
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  1. Clin Infect Dis. (2010) 51 (2): 233-238. doi: 10.1086/653677
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