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Fc gamma receptors (Fc gamma Rs) are key immune regulatory receptors that connect antibody-mediated immune responses to cellular effector functions. They are involved in the control of various immune functions including responses to infections. Genetic polymorphisms of Fc gamma Rs coding genes (FCGR) have been associated with the regulation of HIV infection and progression. In this study, we analyzed the potential impact of five candidate Fc gamma R SNPs on viral control by genotyping 251 HIV controllers and 250 progressors. The rs10800309 AA genotype of the Fc gamma RIIa coding geneFCGR2Awas found to be significantly associated with HIV control and this association was independent ofHLA-B57andHLA-B27(OR, 2.84; 95% CI, 1.20-6.89;P-cor = 0.033). We further confirmed the functional role of this polymorphism by showing an association of this same AA genotype with an increased in vitro Fc gamma RII expression on myeloid cells including dendritic cells (P = 0.0032). Together, these results suggest that the AA genotype of rs10800309 confers an improved immune response through Fc gamma RII upregulation and that this polymorphism may serve as an additional predictive marker of HIV control.

Objective In the semen, both free virus and infected cells are able to establish HIV infection during sexual intercourse. An efficient vaccine should therefore inhibit both infectious states. The aim of this study was to analyze the capacity of broadly neutralizing antibodies (bNAbs) to inhibit HIV transmission by the infected cells. Design/methods We developed an in-vitro model aiming to mimic mucosal HIV transmission via infected cells. PHA-activated CD4+ T cells stained with PKH26 from donor A were infected and co-cultured with CD4+ T cells and dendritic cells from donor B in the presence of bNAbs. Results We showed that dendritic cells were the preferential HIV target cells at early time points in this co-culture model. In the context of this co-culture model where infection and transmission occurred simultaneously, bNAbs efficiently inhibited HIV replication as well as HIV transmission from infected cells to allogenic dendritic cells and CD4+ T cells. Conclusion Overall, our results indicate that dendritic cells, in addition to CD4+ T cells, are key cells that are efficiently infected by HIV and bNAbs are potent inhibitors of infection of both target cells. Future HIV prophylactic vaccine design should develop immune strategies able to prevent the infection of dendritic cells, in addition to the inhibition of CD4+ T-cell infection.

The development of an effective vaccine against HIV-1 has proven to be challenging. Broadly neutralizing antibodies (bNAbs), whilst exhibiting neutralization breadth and potency, are elicited only in a small subset of infected individuals and have yet to be induced by vaccination. Case-control studies of RV144 identified an inverse correlation of HIV-1 infection risk with antibodies (Abs) to the V1V2 region of gp120 with high antibody-dependent cellular cytotoxicity (ADCC) activity. The neutralizing activity of Abs was not found to contribute to this protective outcome. Using primary effector and target cells and primary virus isolates, we studied the ADCC profile of different monoclonal Abs targeting the V1V2 loop of gp120 that had low or no neutralizing activity. We compared their ADCC activity to some bNAbs targeting different regions of gp120. We found that mAbs targeting the V1V2 domain induce up to 60% NK cell mediated lysis of HIV-1 infected PBMCs in a physiologically relevant ADCC model, highlighting the interest in inducing such Abs in future HIV vaccine trials. Our data also suggest that in addition to neutralization, lysis of infected cells by Abs can effectively participate in HIV protection, as suggested by the RV144 immune correlate analysis.

Langerhans cells are specialized sentinels present in the epidermis expressing Langerin, a specific C-type lectin receptor involved in HIV capture and destruction. Recently, the specific mechanism leading to this HIV restriction was discovered. Nevertheless, Langerhans cells can be infected and the way HIV escapes this restriction needs to be unraveled.

Failure of immune reconstitution increases the risk of AIDS or non-AIDS related morbidity and mortality in HIV-1-infected patients. CD3+CD4-CD8- T cells, which are usually described as double negative (DN) T cells, display CD4-like helper and immunoregulatory functions. Here, we have measured the percentage of DN T cells in the immune reconstituted versus non-immune reconstituted HIV-1-infected individuals. We observed that immunological non-responders (INRs) had a low number of DN T cells after long-term antiretroviral therapy (ART) and the number of these cells positively correlated with the CD4+ T cell count. The ART did not result in complete suppression of immune activation recorded by the percentage of CD38+HLA-DR+CD8+T cells in INRs, and a strong inverse correlation was observed between DN T cells and immune activation. A low proportion of TGF-β1+DN T cells was found in INRs. Further mechanism study demonstrated that the level of TGF-β1 producing DN T cells and immune activation had a negative correlation after ART. Taken together, our study suggests that DN T cells control the immunological response in HIV-1-infected patients. These findings expand our understanding of the mechanism of immune reconstitution and could develop specific treatments to return the immune system to homeostasis following initiation of HIV-1 therapy.

Antibodies (Abs) are a critical component of the human immune response against viral infections. In HIV-infected patients, a robust Ab response against the virus develops within months of infection; however, due to numerous strategies, the virus usually escapes the biological effects of the various Abs. Here we provide an overview of the different viral evasion mechanisms, including glycosylation, high mutation rate, and conformational masking by the envelope glycoproteins of the virus. In response to virus infection and to its evolution within a host, “conventional Abs” are generated, and these can also be induced by immunization; generally, these Abs are limited in their neutralization breadth and potency. In contrast, “exceptional Abs” require extended exposure to virus to generate the required hypermutation in the immunoglobulin variable regions, and they occur only in rare HIV-infected individuals, but they display impressive breadth and potency. In this review, we describe the major regions of the HIV envelope spike that are targeted by conventional and exceptional Abs. These include the first, second, and third variable loops (V1, V2, and V3) located at the apex of the envelope trimer, the CD4 binding site, and the membrane-proximal external region of the gp41 ectodomain. Lastly, we discuss the challenging task of HIV immunogen design and approaches for choosing which immunogens might be used to elicit protective Abs.

The HIV epidemic in Cameroon is marked by a broad genetic diversity dominated by circulating recombinant forms (CRFs). Studies performed more than a decade ago in urban settings of Southern Cameroon revealed a dominance of the CRF02_AG and clade A variants in >90% of the infected subjects; however, little is known about the evolving viral variants circulating in this region. To document circulating HIV viral diversity, four regions of the viral genome (gag, PR, reverse transcriptase, env) in 116 HIV-1 positive individuals in Limbe, Southern Cameroon, were PCR-amplified. Sequences obtained at the RT and protease regions were analyzed for mutations that conferred drug resistance using the Stanford Drug Resistance Database. The present study reveals a broad genetic diversity characterized by several unique recombinant forms (URF) accounting for 36% of infections, 48.6% of patients infected with CRF02_AG, and the emergence of CRF22_01A1 in 7.2% of patients. Three out of 15 (20%) treated patients and 13 out of 93 (13.9%) drug naive patients harbor drug resistance mutations to RT inhibitors, while 3.2% of drug naive patients harbor drug resistance mutations associated with protease inhibitors. The high proportion (13.9%) of drug resistance mutations among the drug naive patients reveals the ongoing transmission of these viruses in this region of Cameroon and highlights the need for drug resistance testing before starting treatment for patients infected with HIV-1. J. Med. Virol. 86:385–393, 2014. © 2013 The Authors. Journal of Medical Virology Published by Wiley Periodicals, Inc.