Impact of the Timing of Initiation of Antiretroviral Therapy During Primary HIV-1 Infection on the Decay of Cell-Associated HIV-DNA

Laanani, Moussa; Ghosn, Jade; Essat, Asma; Mélard, Adeline; Seng, Rémonie; Gousset, Marine; Panjo, Henri; Mortier, E.; Girard, Pierre‐Marie; Goujard, Cécile; Meyer, Laurence; Rouzioux, Christine

doi:10.1093/cid/civ171

Cited by 110 publications

(118 citation statements)

References 35 publications

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“…Jain et al (27) showed that early ART (within 6 months of infection) was associated with lower levels of cell-associated HIV DNA and RNA as well as lower levels of CD4 and CD8 T-cell activation. Again, the authors suggested timing of ART to be a critical determinant of reservoir size, consistent with prior studies (11,14,15,(28)(29)(30).…”

Section: Discussionsupporting

confidence: 82%

Monitoring Integration over Time Supports a Role for Cytotoxic T Lymphocytes and Ongoing Replication as Determinants of Reservoir Size

Pinzone

Graf

Lynch

et al. 2016

J Virol

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The dynamics of HIV reservoir accumulation off antiretroviral therapy (ART) is underexplored. Levels of integrated HIV DNA in peripheral blood mononuclear cells (PBMCs) were longitudinally monitored before and after antiviral therapy. HIV integration increased over time in both elite controllers (ECs; n ‫؍‬ 8) and noncontrollers (NCs; n ‫؍‬ 6) before ART, whereas integration remained stable in patients on ART (n ‫؍‬ 4). The median annual fold change was higher in NCs than in ECs and negatively correlated with CD4/CD8 T-cell ratio. Cytotoxic T lymphocyte (CTL) function as assessed by infected CD4 T-cell elimination (ICE) and granzyme B activity did not significantly change over time in ECs, suggesting that the gradual increase in integrated HIV DNA observed in ECs was not a result of progressive loss of immune-mediated control. Also, acutely infected (n ‫؍‬ 7) but not chronically infected (n ‫؍‬ 6) patients exhibited a significant drop in integrated HIV DNA 12 months after ART initiation. In conclusion, in the absence of ART, integrated HIV accumulates over time both in NCs and in ECs, at variable individual rates. Starting ART early in infection leads to a greater drop in integrated HIV DNA than does initiating treatment after years of infection. The increase in integrated HIV DNA over time suggests that early treatment may be of benefit in limiting HIV reservoirs. IMPORTANCEThe establishment of a latent reservoir represents a barrier to cure among HIV-infected individuals. The dynamics of HIV reservoir accumulation over time in patients before antiviral therapy is underexplored, in large part because it is difficult to accurately and reproducibly measure the size of HIV reservoir in this setting. In our study, we compared the dynamics of integrated HIV DNA over time in ECs and NCs before and after ART was initiated. We found that integrated HIV DNA levels progressively increase over time in the absence of ART, but with a higher, albeit variable, rate in NCs compared to ECs. In addition, integrated HIV DNA declines more dramatically when ART is initiated in acute rather than chronic HIV infection, suggesting important differences between acute and chronic infection. Our study highlights the role of HIV replication and CTL control in reservoir accumulation in sanctuary sites and why ART appears to be more effective in acute infection.

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Section: Discussionsupporting

confidence: 82%

Monitoring Integration over Time Supports a Role for Cytotoxic T Lymphocytes and Ongoing Replication as Determinants of Reservoir Size

Pinzone

Graf

Lynch

et al. 2016

J Virol

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“…Failure of HIV DNA to decrease in 12 months post-cART in pTfh and non-pTfh cells of chronically infected patients is not surprising. It is well known that the rate of decay of cell-associated HIV DNA is fastest in patients initiating treatment very early during the acute infection, and even in these situations the decay can take up to 8 months following cART initiation (44)(45)(46). In our study, all patients were chronically HIV infected, and it is likely that HIV DNA decay takes longer than 48 weeks on cART.…”

Section: Discussionmentioning

confidence: 67%

“…In our study, all patients were chronically HIV infected, and it is likely that HIV DNA decay takes longer than 48 weeks on cART. The fast firstphase decay of viral DNA could result from the clearance of activated and productively infected T EM and T TM CD4 T cells (47) rather than the less activated long-living T CM cells (46,47). Further, T EM and T TM CD4 T cells have shorter half-lives and are infected earlier than naive and T CM cells due to their higher level of immune activation and coreceptor expression.…”

Section: Discussionmentioning

confidence: 99%

Peripheral T Follicular Helper Cells Are the Major HIV Reservoir within Central Memory CD4 T Cells in Peripheral Blood from Chronically HIV-Infected Individuals on Combination Antiretroviral Therapy

Pallikkuth

Sharkey

Babič

et al. 2016

J Virol

112

111

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In this study, we examined the peripheral blood (PB) central memory (T CM ) CD4؉ T cell subsets designated peripheral T follicular helper cells (pTfh cells) and non-pTfh cells to assess HIV permissiveness and persistence. Purified pTfh and non-pTfh cells from healthy HIV-negative donors were tested for HIV permissiveness using green fluorescent protein (GFP)-expressing HIV-1NL4-3/Ba-L, followed by viral reactivation using beads coated with anti-CD3/anti-CD28 monoclonal antibodies. The role of pTfh cells in HIV persistence was analyzed in 12 chronically HIV-1 infected patients before and 48 weeks after initiation of raltegravir-containing combination antiretroviral therapy (cART). Total cellular HIV-1 DNA and episomes containing two copies of the viral long terminal repeat (2LTR circles) were analyzed in using droplet digital PCR in the purified pTfh and non-pTfh cells.

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“…Approaches include boosting HIV-specific immunity, reducing inflammation, activating latency, and targeting HIV apoptosis regulatory pathways. 7,[31][32][33] Recent studies also point out that ART initiated during early AHI either prevents loss of (at Fiebig stage I/II) or restores (at Fiebig stage III) mucosal Th17 cells. 34 Consequently, very early ART is associated with normalization of local and systemic immune activation, reversing a hallmark of HIV pathogenesis.…”

Section: Discussionmentioning

confidence: 99%

“…6 This seronegative window is thus of crucial importance for early treatment outcome, vaccine development, and public health. 7,8 Despite the importance of AHI, there are immense difficulties identifying AHI patients for treatment initiation. Patients are often asymptomatic or experience a nonspecific febrile illness; a diagnostic dilemma compounded in the African setting by a significant symptom overlap with malaria.…”

Section: Introductionmentioning

confidence: 99%

A Cytokine Pattern That Differentiates Preseroconversion From Postseroconversion Phases of Primary HIV Infection

Pastor

Parker

Carrillo

et al. 2017

JAIDS Journal of Acquired Immune Deficiency Syndromes

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Background: During acute HIV infection, HIV actively replicates but seroconversion has not yet occurred. Primary HIV infection (PHI) is characterized by a transient nonspecific febrile illness, a massive inflammatory response, and the progressive appearance of anti-HIV-specific antibodies. In this study, we have identified patterns of inflammatory biomarkers associated with the innate immunological reaction before completion of a full humoral response.Methods: A symptom-based screening was used to identify acute HIV infection in the Manhiça District Hospital in Mozambique. Plasma levels of biomarkers were determined by Luminex and enzyme-linked immunosorbent assay. Anti-HIV antibodies were analyzed by flow cytometry and Western blot. Statistical analyses used random forest and logistic regression models.Results: Of 3116 rapid test seronegative or indeterminate individuals, 85 (2.7%) had positive plasma HIV viral load and were enrolled as PHI, of which n = 45 (52.9%), n = 8 (9.4%), n = 12 (14.1%), and n = 20 (23.5%) were classified as Fiebig I-III, IV, V, and VI stages, respectively, by Western blot. Comparison of individuals at early (Fiebig I-IV) and late (Fiebig V-VI) immune stages identified significant differences in the expression level of plasma B-cell activating factor , monocyte chemotactic protein-1, sCD163, and monokine induced by interferon (IFN-g). This cytokine signature classified patients in the preseroconversion phase with a sensitivity of 92.5% and a specificity of 81.2%Conclusions: Identification of a cytokine signature specific for the preseroconversion stage of PHI may help to understand the earliest HIV pathogenic events and identify new potential targets for immunotherapy aimed at modulating the cytokine response to HIV infection.

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Impact of the Timing of Initiation of Antiretroviral Therapy During Primary HIV-1 Infection on the Decay of Cell-Associated HIV-DNA

Abstract: This study provides strong arguments in favor of cART initiation at the earliest possible time point after HIV infection.

Cited by 110 publications

References 35 publications

Monitoring Integration over Time Supports a Role for Cytotoxic T Lymphocytes and Ongoing Replication as Determinants of Reservoir Size

Monitoring Integration over Time Supports a Role for Cytotoxic T Lymphocytes and Ongoing Replication as Determinants of Reservoir Size

Peripheral T Follicular Helper Cells Are the Major HIV Reservoir within Central Memory CD4 T Cells in Peripheral Blood from Chronically HIV-Infected Individuals on Combination Antiretroviral Therapy

A Cytokine Pattern That Differentiates Preseroconversion From Postseroconversion Phases of Primary HIV Infection

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