Combination of HIV‐1–Specific CD4 Th1 Cell Responses and IgG2 Antibodies Is the Best Predictor for Persistence of Long‐Term Nonprogression

Martinez, Valérie; Costagliola, Dominique; Bonduelle, Olivia; Ngo, Nicole; Schnuriger, Aurélie; Théodorou, Ioannis; Clauvel, Jean‐Pierre; Sicard, Didier; Agut, Henri; Debré, Patrice; Rouzioux, Christine; Autran, Brigitte

doi:10.1086/430320

Cited by 106 publications

(102 citation statements)

References 60 publications

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“…Two studies from the same French cohort linked gp41-specific IgG2 and CD4 ϩ Th1 responses with long-term nonprogression (35,36), and Lal et al found an association between the absence of IgG2 antibodies to gp41 and clinical disease (14). These results are consistent with our observation that IgG2 antibodies to gp41 are enriched among ECs with protective HLA alleles.…”

Section: Discussionsupporting

confidence: 92%

Divergent Antibody Subclass and Specificity Profiles but Not Protective HLA-B Alleles Are Associated with Variable Antibody Effector Function among HIV-1 Controllers

Lai

Licht

Dugast

et al. 2014

J Virol

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Understanding the coordination between humoral and cellular immune responses may be the key to developing protective vaccines, and because genetic studies of long-term HIV-1 nonprogressors have associated specific HLA-B alleles with spontaneous control of viral replication, this subject group presents an opportunity to investigate relationships between arms of the adaptive immune system. Given evidence suggesting that cellular immunity may play a role in viral suppression, we sought to determine whether and how the humoral immune response might vary among controllers. Significantly, Fc-mediated antibody effector functions have likewise been associated with durable viral control. In this study, we compared the effector function and biophysical features of HIV-specific antibodies in a cohort of controllers with and without protective HLA-B alleles in order to investigate whether there was evidence for multiple paths to HIV-1 control, or whether cellular and humoral arms of immunity might exhibit coordinated profiles. However, with the exception of IgG2 antibodies to gp41, HLA status was not associated with divergent humoral responses. This finding did not result from uniform antibody responses across subjects, as controllers could be regrouped according to strong differences in their HIV-specific antibody subclass specificity profiles. These divergent antibody profiles were further associated with significant differences in nonneutralizing antibody effector function, with levels of HIVspecific IgG1 acting as the major distinguishing factor. Thus, while HLA background among controllers was associated with minimal differences in humoral function, antibody subclass and specificity profiles were associated with divergent effector function, suggesting that these features could be used to make functional predictions. Because these nonneutralizing antibody activities have been associated with spontaneous viral control, reduced viral load, and nonprogression in infected subjects and protection in vaccinated subjects, understanding the specific features of IgGs with potentiated effector function may be critical to vaccine and therapeutic antibody development. IMPORTANCEIn this study, we investigated whether the humoral and cellular arms of adaptive immunity exhibit coordinated or compensatory activity by studying the antibody response among HIV-1 controllers with different genetic backgrounds.

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Section: Discussionsupporting

confidence: 92%

Divergent Antibody Subclass and Specificity Profiles but Not Protective HLA-B Alleles Are Associated with Variable Antibody Effector Function among HIV-1 Controllers

Lai

Licht

Dugast

et al. 2014

J Virol

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“…3) (81). The range of HIV DNA levels was smaller than the range of HIV RNA levels, but nonetheless identified several patient subgroups in large cohorts; in particular, LTNPs and elite controllers had significantly lower HIV DNA levels than pro- (61,(88)(89)(90) (Fig. 3).…”

Section: Other Tissues and Fluidsmentioning

confidence: 99%

“…Patients who naturally control HIV infection (long-term nonprogressors and elite controllers) have very low and stable total HIV DNA levels, with median values of 2.3 and 1.5 log 10 copies/ 10 6 PBMC reported in, respectively, 66 and 15 patients (88)(89)(90). Similarly, posttreatment controllers in the VISCONTI cohort, for whom treatment was initiated early during the primary infection and long-term viral control after treatment interruption was maintained, had low total HIV DNA levels (median, 1.71 log 10 copies/10 6 PBMC; 14 patients) (91,92) (Fig.…”

Section: Total Hiv Dna In Blood During Untreated Infectionmentioning

confidence: 99%

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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 relevance for functional CD4+ T-cell help in the maintenance of effective CTL populations has recently also been reported for viral infections other than HIV, including EBV and CMV infections [134,135]. The potential importance of virusspecific T helper cell activity is further highlighted by studies that have associated the presence of gp41-specific antibodies with CD4+ T-cell responses to Gagp24 [136,137]. Regardless of the well-documented anti-viral effects of neutralizing Ab responses [138] general antibody-responses have not emerged as strong markers of HIV control.…”

Section: Hiv Disease Markers Associated With Virus-specific Cellular mentioning

confidence: 92%

Virological, Immune and Host genetics Markers in the Control of HIV Infection

et al. 2009

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Abstract. HIV infection, if left untreated, leads in most cases to the development of wide immune deterioration, opportunistic infections and eventually AIDS and death. The identification of individuals who despite persisting infection show no or few signs of HIV disease progression has spurred hopes that an effective HIV vaccine could be attainable. The design of such a vaccine will greatly depend on the precise definition of disease markers, host genetic and immune characteristics that mediate relative in vivo control of this virus. Accordingly, a number of viral factors and host genetic characteristics have been shown to play a crucial role in the control of HIV disease by delaying progression to AIDS or even preventing infection. There is also an improved understanding of humoral and cellular immune responses in terms of specificity, functional repertoire, longevity and tissue distribution and their ability to contain HIV replication. However, the definition of good immune correlates unequivocally and causally associated with protection or disease progression remains elusive. Here we review work on viral factors, host genetic markers and immunological determinants that have been identified in individuals with superior control of HIV infection or in subjects who remain uninfected despite frequent exposure to the viral pathogen.

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Combination of HIV‐1–Specific CD4 Th1 Cell Responses and IgG2 Antibodies Is the Best Predictor for Persistence of Long‐Term Nonprogression

Abstract: HIV-1-specific CD4 Th1 responses combined with IgG2 antibodies and IFN- gamma -producing CD4 Th1 cells are better predictors of long-term nonprogression than are virus parameters, host genes, or HIV-1-specific CD4 Th1 or CD8 T cell proliferation.

Cited by 106 publications

References 60 publications

Divergent Antibody Subclass and Specificity Profiles but Not Protective HLA-B Alleles Are Associated with Variable Antibody Effector Function among HIV-1 Controllers

Divergent Antibody Subclass and Specificity Profiles but Not Protective HLA-B Alleles Are Associated with Variable Antibody Effector Function among HIV-1 Controllers

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

Virological, Immune and Host genetics Markers in the Control of HIV Infection

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