CD4 Cell Count and HIV DNA Level Are Independent Predictors of Disease Progression after Primary HIV Type 1 Infection in Untreated Patients

Goujard, Cécile; Bonarek, M.; Meyer, Laurence; Bonnet, Fabrice; Chaix, Marie‐Laure; Deveau, Christiane; Sinet, Martine; Galimand, Julie; Delfraissy, Jean‐François; Venet, Alain; Rouzioux, Christine; Morlat, Philippe

doi:10.1086/500213

Cited by 191 publications

(152 citation statements)

References 34 publications

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“…The levels of cell-associated HIV-1 DNA have been shown to predict progression to disease and the capacity to control infection after treatment interruption (19,22,(51)(52)(53). Although measurement of total HIV-1 DNA levels may take into account many copies of replication-deficient viruses, it is likely that under conditions of very low levels of viral replication, as in HICs, differences in the levels of HIV-1 DNA probably maintain proportionality between replication-competent and noncompe-tent proviruses, as recently observed in treated patients (54).…”

Section: Discussionmentioning

confidence: 99%

Long-Term Spontaneous Control of HIV-1 Is Related to Low Frequency of Infected Cells and Inefficient Viral Reactivation

Noël

Peña

David

et al. 2016

J Virol

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HIV establishes reservoirs of infected cells that persist despite effective antiretroviral therapy (ART). In most patients, the virus begins to replicate soon after treatment interruption. However, a low frequency of infected cells at the time of treatment interruption has been associated with delayed viral rebound. Likewise, individuals who control the infection spontaneously, so-called HIV-1 controllers (HICs), carry particularly low levels of infected cells. It is unclear, however, whether and how this small number of infected cells contributes to durable viral control. Here we compared 38 HICs with 12 patients on effective combined antiretroviral therapy (cART) and found that the low frequency of infected cells in the former subjects was associated both with less efficient viral reactivation in resting CD4؉ T cells and with less efficient virion production ex vivo. We also found that a potent HIV-specific CD8 ؉ T cell response was present only in those HICs whose CD4 ؉ T cells produced virus ex vivo. Long-term spontaneous control of HIV infection in HICs thus appears to be sustained on the basis of the inefficient reactivation of viruses from a limited number of infected cells and the capacity of HICs to activate a potent HIV-specific CD8؉ T cell response to counteract efficient viral reactivation events. IMPORTANCEThere is a strong scientific interest in developing strategies to eradicate the HIV-1 reservoir. Very rare HIV-1-infected patients are able to spontaneously control viremia for long periods of time (HIV-1 controllers [HICs]) and are put forward as a model of HIV-1 remission. Here, we show that the low viral reservoirs found in HICs are a critical part of the mechanisms underlying viral control and result in a lower probability of HIV-1 reactivation events, resulting in limited HIV-1 release and spread. We found that those HICs in whom viral reactivation and spread from CD4 ؉ T cells in vitro were the most difficult were those with diminished CD8 ؉ T cell responses. These results suggest that, in some settings, low HIV-1 reservoirs decisively contribute to at least the temporary control of infection without antiretroviral therapy. We believe that this work provides information of relevance in the context of the search for HIV-1 remission.

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Section: Discussionmentioning

confidence: 99%

Long-Term Spontaneous Control of HIV-1 Is Related to Low Frequency of Infected Cells and Inefficient Viral Reactivation

Noël

Peña

David

et al. 2016

J Virol

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“…in blood was 2.8 to 3.2 log 10 copies/10 6 PBMC among patients in the French PRIMO cohort (Fig. 3) and the Ivorian PRIMOCI cohort (674 and 200 patients, respectively) (80)(81)(82)(83).…”

Section: Total Hiv Dna In Blood During Untreated Infectionmentioning

confidence: 91%

Total HIV-1 DNA, a Marker of Viral Reservoir Dynamics with Clinical Implications

et al. 2016

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SUMMARYHIV-1 DNA persists in infected cells despite combined antiretroviral therapy (cART), forming viral reservoirs. Recent trials of strategies targeting latent HIV reservoirs have rekindled hopes of curing HIV infection, and reliable markers are thus needed to evaluate viral reservoirs. Total HIV DNA quantification is simple, standardized, sensitive, and reproducible. Total HIV DNA load influences the course of the infection and is therefore clinically relevant. In particular, it is predictive of progression to AIDS and death, independently of HIV RNA load and the CD4 cell count. Baseline total HIV DNA load is predictive of the response to cART. It declines during cART but remains quantifiable, at a level that reflects both the history of infection (HIV RNA zenith, CD4 cell count nadir) and treatment efficacy (residual viremia, cumulative viremia, immune restoration, immune cell activation). Total HIV DNA load in blood is also predictive of the presence and severity of some HIV-1-associated end-organ disorders. It can be useful to guide individual treatment, notably, therapeutic de-escalation. Although it does not distinguish between replication-competent and -defective latent viruses, the total HIV DNA load in blood, tissues, and cells provides insights into HIV pathogenesis, probably because all viral forms participate in host cell activation and HIV pathogenesis. Total HIV DNA is thus a biomarker of HIV reservoirs, which can be defined as all infected cells and tissues containing all forms of HIV persistence that participate in pathogenesis. This participation may occur through the production of new virions, creating new cycles of infection and disseminating infected cells; maintenance or amplification of reservoirs by homeostatic cell proliferation; and viral transcription and synthesis of viral proteins without new virion production. These proteins can induce immune activation, thus participating in the vicious circle of HIV pathogenesis.

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“…The patients studied presented with PHI when enrolled in the multicenter ANRS PRIMO Cohort (22). The PRIMO study protocol was approved by the Paris Cochin Ethics Committee, and all subjects gave their written informed consent.…”

Section: Methodsmentioning

confidence: 99%

Low Frequency of CXCR4-Using Viruses in Patients at the Time of Primary Non-Subtype-B HIV-1 Infection

et al. 2010

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We used genotypic and phenotypic assays to estimate the frequency of X4/DM viruses in 131 patients infected with non-subtype-B viruses at the time of primary HIV-1 infection (PHI). All patients were enrolled in the French PRIMO Cohort from 1996 to 2007. Most strains belonged to CRF02_AG (51.1%) and subtype A (14.5%). Sixteen viruses (12.2%) were classified as CXCR4 tropic ("X4 strains") by the combined criteria of amino acids 11 and 25 of the V3 loop (11/25) and net charge rules and/or the SVMgeno2pheno 10% algorithm: 6 strains by the combined genotypic rule, 7 by the SVMgeno2pheno 10% algorithm, and 3, clustering in subtype D, by both algorithms. However, only one strain (0.8%), belonging to subtype A, was defined as a dual-tropic (DM) virus by the phenotypic assay. The 67 CRF02_AG strains included 2 classified as X4 strains by the combined genotypic rule (3%) and 2 others classified as X4 strains by SVMgeno2pheno 10% (3%), but none of these 4 strains was an X4 or DM strain according to the phenotypic assay. These results suggest that the cellular virus reservoir was established with X4 strains in very few non-subtype-B-infected patients at the time of PHI. Genotypic predictions can overestimate the proportion of non-subtype-B X4 viruses at PHI.

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CD4 Cell Count and HIV DNA Level Are Independent Predictors of Disease Progression after Primary HIV Type 1 Infection in Untreated Patients

Abstract: Both a low initial CD4 cell count and a high HIV DNA level are predictive of rapid progression of untreated primary HIV-1 infection. Affected patients may therefore benefit from close clinical and laboratory monitoring and/or early administration of treatment.

Cited by 191 publications

References 34 publications

Long-Term Spontaneous Control of HIV-1 Is Related to Low Frequency of Infected Cells and Inefficient Viral Reactivation

Long-Term Spontaneous Control of HIV-1 Is Related to Low Frequency of Infected Cells and Inefficient Viral Reactivation

Total HIV-1 DNA, a Marker of Viral Reservoir Dynamics with Clinical Implications

Low Frequency of CXCR4-Using Viruses in Patients at the Time of Primary Non-Subtype-B HIV-1 Infection

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