Escape of HIV-1 envelope glycoprotein from the restriction of infection by IFITM3.

Interferon-induced transmembrane protein 3 (IFITM3) is a cellular factor that reduces HIV-1 infectivity by an incompletely understood mechanism. We show here that viruses differing only in the envelope glycoprotein (Env) expressed on their surface have different sensitivities to IFITM3. Measurements of the sensitivity of viruses to neutralizing antibodies showed that IFITM3 increased the sensitivity of IFITM3-sensitive viruses to PG16, which targets the V1V2 loop, suggesting that IFITM3 promotes exposure of the PG16 epitope of IFITM3-sensitive viruses. Exchanges of V1V2 loops between the Env proteins of sensitive and resistant viruses revealed that V1V2 and V3 act together to modulate viral sensitivity to IFITM3. Co-immunoprecipitation experiments showed that IFITM3 interacted with both the precursor (gp160) and cleaved (gp120) forms of Env from IFITM3-sensitive viruses, but only with the precursor (gp160) form of Env from IFITM3-resistant viruses. This finding suggests that the interaction between the Env of resistant viruses and IFITM3 was inhibited once Env had been processed in the Golgi apparatus. This hypothesis was supported by immunofluorescence experiments, which showed a strong colocalization of IFITM3 with the Env of sensitive viruses, but only weak colocalization with the Env of resistant viruses on the plasma membrane of virus-producing cells. Together, these results indicate that IFITM3 interacts with Env, inducing conformational changes that may decrease viral infectivity. This antiviral action is, nevertheless, modulated by the nature of the Env, in particular its V1V2 and V3 loops, which after maturation may be able to escape this interaction.IMPORTANCE Interferon-induced transmembrane protein 3 (IFITM3) is a cellular factor that reduces HIV-1 infectivity by an incompletely understood mechanism. This study aimed to elucidate the role of the HIV-1 envelope glycoprotein (Env) in determining viral susceptibility to IFITM3. We found that viruses differing only in Env expressed on their surface had different sensitivities to IFITM3. By comparing the Env proteins of viruses that were highly sensitive or resistant to IFITM3, we obtained new insight in the mechanisms by which HIV-1 escapes this protein. We showed that IFITM3 interacts with the Env protein of sensitive viruses in virion-producing cells, inducing conformational changes that may decrease viral infectivity. However, this antiviral action is modulated by the nature of Env, particularly the V1V2 and V3 loops, which may be able to escape this interaction after processing in the Golgi.

Sensitivity to Broadly Neutralizing Antibodies of Recently Transmitted HIV-1 Clade CRF02_AG Viruses with a Focus on Evolution over Time.

Broadly neutralizing antibodies (bnAbs) are promising agents for prevention and/or treatment of HIV-1 infection. However, the diversity among HIV-1 envelope (Env) glycoproteins impacts bnAb potency and breadth. Neutralization data on the CRF02_AG clade are scarce although it is highly prevalent in West Africa and Europe. We assessed the sensitivity to bnAbs of a panel of 33 early transmitted CRF02_AG viruses over a 15-year period of the French epidemic (1997 to 2012). Env pseudotyped CRF02_AG viruses were best neutralized by the CD4 binding site (CD4bs)-directed bnAbs (VRC01, 3BNC117, NIH45-46G54W, and N6) and the gp41 membrane-proximal external region (MPER)-directed bnAb 10E8 in terms of both potency and breadth. We observed a higher resistance to bnAbs targeting the V1V2-glycan region (PG9 and PGT145) and the V3-glycan region (PGT121 and 10-1074). Combinations were required to achieve full coverage across this subtype. We observed increased resistance to bnAbs targeting the CD4bs linked to the diversification of CRF02_AG Env over the course of the epidemic, a phenomenon which was previously described for subtypes B and C. These data on the sensitivity to bnAbs of CRF02_AG viruses, including only recently transmitted viruses, will inform future passive immunization studies. Considering the drift of the HIV-1 species toward higher resistance to neutralizing antibodies, it appears necessary to keep updating existing panels for evaluation of future vaccine and passive immunization studies.IMPORTANCE Major progress occurred during the last decade leading to the isolation of human monoclonal antibodies, termed broadly neutralizing antibodies (bnAbs) due to their capacity to neutralize various strains of HIV-1. Several clinical trials are under way in order to evaluate their efficacy in preventive or therapeutic strategies. However, no single bnAb is active against 100% of strains. It is important to gather data on the sensitivity to neutralizing antibodies of all genotypes, especially those more widespread in regions where the prevalence of HIV-1 infection is high. Here, we assembled a large panel of clade CRF02_AG viruses, the most frequent genotype circulating in West Africa and the second most frequent found in several European countries. We evaluated their sensitivities to bnAbs, including those most advanced in clinical trials, and looked for the best combinations. In addition, we observed a trend toward increased resistance to bnAbs over the course of the epidemic.

Evolution of the Envelope Glycoprotein of HIV-1 Clade B toward Higher Infectious Properties over the Course of the Epidemic.

We showed previously that during the HIV/AIDS epidemic, the envelope glycoprotein (Env) of HIV-1, and in particular, the gp120 subunit, evolved toward an increased resistance to neutralizing antibodies at a population level. Here, we considered whether the antigenic evolution of the HIV-1 Env is associated with modifications of its functional properties, focusing on cell entry efficacy and interactions with the receptor and coreceptors. We tested the infectivity of a panel of Env-pseudotyped viruses derived from patients infected by subtype B viruses at three periods of the epidemic (1987 to 1991, 1996 to 2000, and 2006 to 2010). Pseudotyped viruses harboring Env from patients infected during the most recent period were approximately 10-fold more infectious in cell culture than those from patients infected at the beginning of the epidemic. This was associated with faster viral entry kinetics: contemporary viruses entered target cells approximately twice as fast as historical viruses. Contemporary viruses were also twice as resistant as historical viruses to the fusion inhibitor enfuvirtide. Resistance to enfuvirtide correlated with a resistance to CCR5 antagonists, suggesting that contemporary viruses expanded their CCR5 usage efficiency. Viruses were equally captured by DC-SIGN, but after binding to DC-SIGN, contemporary viruses infected target cells more efficiently than historical viruses. Thus, we report evidence that the infectious properties of the envelope glycoprotein of HIV-1 increased during the course of the epidemic. It is plausible that these changes affected viral fitness during the transmission process and might have contributed to an increasing virulence of HIV-1.IMPORTANCE Following primary infection by HIV-1, neutralizing antibodies (NAbs) exert selective pressure on the HIV-1 envelope glycoprotein (Env), driving the evolution of the viral population. Previous studies suggested that, as a consequence, Env has evolved at the HIV species level since the start of the epidemic so as to display greater resistance to NAbs. Here, we investigated whether the antigenic evolution of the HIV-1 Env is associated with modifications of its functional properties, focusing on cell entry efficacy and interactions with the receptor and coreceptors. Our data provide evidence that the infectious properties of the HIV-1 Env increased during the course of the epidemic. These changes may have contributed to increasing virulence of HIV-1 and an optimization of transmission between individuals.

Buffering deleterious polymorphisms in highly constrained parts of HIV-1 envelope by flexible regions.

BACKGROUND: Covariation is an essential process that leads to coevolution of parts of proteins and genomes. In organisms subject to strong selective pressure, coevolution is central to keep the balance between the opposite requirements of antigenic variation and retention of functionality. Being the viral component most exposed to the external environment, the HIV-1 glycoprotein gp120 constitutes the main target of the immune response. Accordingly its more external portions are characterised by extensive sequence heterogeneity fostering constant antigenic variation. RESULTS: We report that a single polymorphism, present at the level of the viral population in the conserved internal region C2, was sufficient to totally abolish Env functionality when introduced in an exogenous genetic context. The prominent defect of the non-functional protein is a block occurring after recognition of the co-receptor CCR5, likely due to an interference with the subsequent conformational changes that lead to membrane fusion. We also report that the presence of compensatory polymorphisms at the level of the external and hypervariable region V3 fully restored the functionality of the protein. The functional revertant presents different antigenic profiles and sensitivity to the entry inhibitor TAK 779. CONCLUSIONS: Our data suggest that variable regions, besides harbouring intrinsic extensive antigenic diversity, can also contribute to sequence diversification in more structurally constrained parts of the gp120 by buffering the deleterious effect of polymorphisms, further increasing the genetic flexibility of the protein and the antigenic repertoire of the viral population.

Evidence for a continuous drift of the HIV-1 species towards higher resistance to neutralizing antibodies over the course of the epidemic.

We compared the neutralization sensitivity of early/transmitted HIV-1 variants from patients infected by subtype B viruses at 3 periods of the epidemic (1987-1991, 1996-2000, 2006-2010). Infectious pseudotyped viruses expressing envelope glycoproteins representative of the viral quasi-species infecting each patient were tested for sensitivity to neutralization by pools of sera from HIV-1 chronically infected patients and by an updated panel of 13 human monoclonal neutralizing antibodies (HuMoNAbs). A progressive significantly enhanced resistance to neutralization was observed over calendar time, by both human sera and most of the HuMoNAbs tested (b12, VRC01, VRC03, NIH45-46(G54W), PG9, PG16, PGT121, PGT128, PGT145). Despite this evolution, a combination of two HuMoNAbs (NIH45-46(G54W) and PGT128) still would efficiently neutralize the most contemporary transmitted variants. In addition, we observed a significant reduction of the heterologous neutralizing activity of sera from individuals infected most recently (2003-2007) compared to patients infected earlier (1987-1991), suggesting that the increasing resistance of the HIV species to neutralization over time coincided with a decreased immunogenicity. These data provide evidence for an ongoing adaptation of the HIV-1 species to the humoral immunity of the human population, which may add an additional obstacle to the design of an efficient HIV-1 vaccine.

Role of Viral Envelope Proteins in Determining Susceptibility of Viruses to IFITM Proteins.

Interferon-induced transmembrane proteins (IFITMs) are a family of proteins which inhibit infections of various enveloped viruses. While their general mechanism of inhibition seems to be non-specific, involving the tightening of membrane structures to prevent fusion between the viral envelope and cell membrane, numerous studies have underscored the importance of viral envelope proteins in determining the susceptibility of viruses to IFITMs. Mutations in envelope proteins may lead to viral escape from direct interaction with IFITM proteins or result in indirect resistance by modifying the viral entry pathway, allowing the virus to modulate its exposure to IFITMs. In a broader context, the nature of viral envelope proteins and their interaction with IFITMs can play a crucial role in the context of adaptive immunity, leading to viral envelope proteins that are more susceptible to antibody neutralization. The precise mechanisms underlying these observations remain unclear, and further studies in this field could contribute to a better understanding of how IFITMs control viral infections.

The role of neutralizing antibodies in prevention of HIV-1 infection: what can we learn from the mother-to-child transmission context?

In most viral infections, protection through existing vaccines is linked to the presence of vaccine-induced neutralizing antibodies (NAbs). However, more than 30 years after the identification of AIDS, the design of an immunogen able to induce antibodies that would neutralize the highly diverse HIV-1 variants remains one of the most puzzling challenges of the human microbiology. The role of antibodies in protection against HIV-1 can be studied in a natural situation that is the mother-to-child transmission (MTCT) context. Indeed, at least at the end of pregnancy, maternal antibodies of the IgG class are passively transferred to the fetus protecting the neonate from new infections during the first weeks or months of life. During the last few years, strong data, presented in this review, have suggested that some NAbs might confer protection toward neonatal HIV-1 infection. In cases of transmission, it has been shown that the viral population that is transmitted from the mother to the infant is usually homogeneous, genetically restricted and resistant to the maternal HIV-1-specific antibodies. Although the breath of neutralization was not associated with protection, it has not been excluded that NAbs toward specific HIV-1 strains might be associated with a lower rate of MTCT. A better identification of the antibody specificities that could mediate protection toward MTCT of HIV-1 would provide important insights into the antibody responses that would be useful for vaccine development. The most convincing data suggesting that NAbs might confer protection against HIV-1 infection have been obtained by experiments of passive immunization of newborn macaques with the first generation of human monoclonal broadly neutralizing antibodies (HuMoNAbs). However, these studies, which included only a few selected subtype B challenge viruses, provide data limited to protection against a very restricted number of isolates and therefore have limitations in addressing the hypervariability of HIV-1. The recent identification of highly potent second-generation cross-clade HuMoNAbs provides a new opportunity to evaluate the efficacy of passive immunization to prevent MTCT of HIV-1.

The breadth and titer of maternal HIV-1-specific heterologous neutralizing antibodies are not associated with a lower rate of mother-to-child transmission of HIV-1.

It has been hypothesized that neutralizing antibodies (NAbs) should have broad specificity to be effective in protection against diverse HIV-1 variants. The mother-to-child transmission model of HIV-1 provides the opportunity to examine whether the breadth of maternal NAbs is associated with protection of infants from infection. Samples were obtained at delivery from 57 transmitting mothers (T) matched with 57 nontransmitting mothers (NT) enrolled in the multicenter French perinatal cohort (ANRS EPF CO1) between 1990 and 1996. Sixty-eight (59.6%) and 46 (40.4%) women were infected by B and non-B viruses, respectively. Neutralization assays were carried out with TZM-bl cells, using a panel of 10 primary isolates of 6 clades (A, B, C, F, CRF01_AE, and CRF02_AG), selected for their moderate or low sensitivity to neutralization. Neutralization breadths were not statistically different between T and NT mothers. However, a few statistically significant differences were observed, with higher frequencies or titers of NAbs toward several individual strains for NT mothers when the clade B-infected or non-clade B-infected mothers were analyzed separately. Our study confirms that the breadth of maternal NAbs is not associated with protection of infants from infection.

Anti-V1/V3-glycan broadly HIV-1 neutralizing antibodies in a post-treatment controller.

HIV-1 broadly neutralizing antibodies (bNAbs) can decrease viremia but are usually unable to counteract autologous viruses escaping the antibody pressure. Nonetheless, bNAbs may contribute to natural HIV-1 control in individuals off antiretroviral therapy (ART). Here, we describe a bNAb B cell lineage elicited in a post-treatment controller (PTC) that exhibits broad seroneutralization and show that a representative antibody from this lineage, EPTC112, targets a quaternary epitope in the glycan-V3 loop supersite of the HIV-1 envelope glycoprotein. The cryo-EM structure of EPTC112 complexed with soluble BG505 SOSIP.664 envelope trimers revealed interactions with N301- and N156-branched N-glycans and the 324GDIR327 V3 loop motif. Although the sole contemporaneous virus circulating in this PTC was resistant to EPTC112, it was potently neutralized by autologous plasma IgG antibodies. Our findings illuminate how cross-neutralizing antibodies can alter the HIV-1 infection course in PTCs and may control viremia off-ART, supporting their role in functional HIV-1 cure strategies.

Naturally occurring substitutions of conserved residues in human immunodeficiency virus type 1 variants of different clades are involved in PG9 and PG16 resistance to neutralization.

The recently described anti-human immunodeficiency virus type 1 (HIV-1) human mAb PG9 and PG16 are cross-clade broadly neutralizing. Therefore, it can be postulated that the targeted epitope(s) are highly conserved among variants of the entire group M. We analysed the sensitivity to PG9 and PG16 of pseudotyped viruses carrying envelope glycoproteins from the viral quasispecies of three HIV-1 clade CRF01_AE-infected patients. The broad heterogeneity in sensitivity to PG9 and PG16, despite closely genetically related envelope glycoproteins issued from single individuals, allowed us to identify two gp120 cross-clade conserved residues, a lysine at position 168 in the V2 loop and an isoleucine at position 215 in the C2 region, whose substitutions were associated with resistance to PG9 and PG16. By site-directed mutagenesis, we confirmed both in clades B and CRF01_AE that the substitutions K168E and I215M have a major impact on PG9 and PG16 neutralization sensitivity of pseudotyped viruses.

The V1V2 domain and an N-linked glycosylation site in the V3 loop of the HIV-1 envelope glycoprotein modulate neutralization sensitivity to the human broadly neutralizing antibody 2G12.

The broadly neutralizing human monoclonal antibody 2G12 binds to a carbohydrate-dependent epitope involving three major potential N-linked glycosylation sites (PNGS) of gp120 (N295, N332, and N392). Through analysis of the sensitivity to 2G12 of pseudotyped viruses carrying envelope proteins from HIV-1 clade B-infected long-term nonprogressors, we selected two naturally occurring env clones with opposite sensitivities to 2G12, albeit harboring the 3 particular PNGS known to be essential for 2G12 binding (N295, N332, and N392). The resistant clone presented a long and potentially heavily glycosylated V1V2 loop and an additional PNGS (N302) in the V3 loop. The sensitive clone harbored a short V1V2 loop and lacked the PNGS at N302. We created chimeric envelope genes by swapping the V1V2 domains of the two env clones. The influence of N302 on 2G12 sensitivity was assessed by PCR-based site-directed mutagenesis. Both the exchange of the V1V2 domain and the introduction of the PNGS at N302 on the 2G12-sensitive clone induced a significant decrease in sensitivity to 2G12. In contrast, the reverse V1V2 exchange and the removal of the PNGS at N302 on the 2G12-resistant clone increased sensitivity to 2G12, confirming the influence of these regions on 2G12 sensitivity. Our results, supported by a molecular-modeling study, suggest that both the V1V2 loop and an additional PNGS in V3 might limit access to the 2G12 epitope.

Epitope convergence of broadly HIV-1 neutralizing IgA and IgG antibody lineages in a viremic controller.

Decrypting the B cell ontogeny of HIV-1 broadly neutralizing antibodies (bNAbs) is paramount for vaccine design. Here, we characterized IgA and IgG bNAbs of three distinct B cell lineages in a viremic controller, two of which comprised only IgG+ or IgA+ blood memory B cells; the third combined both IgG and IgA clonal variants. 7-269 bNAb in the IgA-only lineage displayed the highest neutralizing capacity despite limited somatic mutation, and delayed viral rebound in humanized mice. bNAbs in all three lineages targeted the N332 glycan supersite. The 2.8-Å resolution cryo-EM structure of 7-269-BG505 SOSIP.664 complex showed a similar pose as 2G12, on an epitope mainly composed of sugar residues comprising the N332 and N295 glycans. Binding and cryo-EM structural analyses showed that antibodies from the two other lineages interact mostly with glycans N332 and N386. Hence, multiple B cell lineages of IgG and IgA bNAbs focused on a unique HIV-1 site of vulnerability can codevelop in HIV-1 viremic controllers.

[Neutralizing antibodies and human immunodeficiency virus type 1 (HIV-1) infection]. / Rôle des anticorps neutralisants dans l'infection par le virus de l'immunodéficience humaine de type 1 (VIH-1).

Most viral vaccines induce the production of neutralizing antibodies that prevent infection. In the case of HIV-1, no immunogen is able to generate antibodies that neutralize the highly diverse variants. Nevertheless, studies conducted these recent years greatly improved our understanding of the role of these antibodies during natural infection, the mechanisms developed by the virus to escape neutralization, and the modes of action of some rare antibodies with broad specificity. If neutralizing anibodies do not seem to play a major role in controlling the disease progression, we now know that several broadly neutralizing antibodies are able to confer sterilizing immunity in experimental animal models, even at concentrations close to those found in some infected individuals. The best characterized antibodies recognize conserved envelope epitopes, such as the CD4 receptor binding site, the membrane-proximal external region (MPER) of gp41, a glycan-dependent epitope, and a quaternary epitope of the trimeric envelope glycoprotein spikes. However, other epitopes targeted by broadly neutralizing antibodies remain to be identified. Their characterization is a major step towards the development of immunogens presenting major neutralization epitopes.

A Comparison of Cell Activation, Exhaustion, and Expression of HIV Coreceptors and Restriction Factors in HIV-1- and HIV-2-Infected Nonprogressors.

Human immunodeficiency viruses induce rare attenuated diseases due either to HIV-1 in the exceptional long-term nonprogressors (LTNPs) or to HIV-2 in West Africa. To better understand characteristics of these two disease types we performed a multiplex comparative analysis of cell activation, exhaustion, and expression of coreceptors and restriction factors in CD4 T cells susceptible to harbor those viruses. We analyzed by flow cytometry the expression of HLA-DR, PD1, CCR5, CXCR6, SAMHD1, Blimp-1, and TRIM5α on CD4 T cell subsets from 10 HIV-1+ LTNPs and 14 HIV-2+ (12 nonprogressors and 2 progressors) of the ANRS CO-15 and CO-5 cohorts, respectively, and 12 HIV- healthy donors (HD). The V3 loop of the HIV-1 envelope from 6 HIV-1+ LTNPs was sequenced to determine the CXCR6-binding capacity. Proportions of HLA-DR+ and PD1+ cells were higher in memory CD4 T subsets from HIV-1 LTNPs compared with HIV-2 and HD. Similar findings were observed for CCR5+ cells although limited to central-memory CD4 T cell (TCM) and follicular helper T cell subsets, whereas all major subsets from HIV-1 LTNPs contained less CXCR6+ cells compared with HIV-2. All six V3 loop sequences from HIV-1 LTNPs contained a proline at position 326. Proportions of SAMHD1+ cells were higher in all resting CD4 T subsets from HIV-1 LTNPs compared with the other groups, whereas Blimp-1+ and Trim5α+ cells did not differ. The CD4 T cell subsets from HIV-1 LTNPs differ from those of HIV-2-infected subjects by higher levels of activation, exhaustion, and SAMHD1 expression that can reflect the distinct patterns of host/virus relationships.

Differential utilization of CD4+ by transmitted/founder and chronic envelope glycoproteins in a MSM HIV-1 subtype B transmission cluster.

OBJECTIVE: HIV-1 transmission leads to a genetic bottleneck, with one or a few variants of the donor quasispecies establishing an infection in the new host. We aimed to characterize this bottleneck in more detail, by comparing the properties of HIV envelope glycoproteins from acute and chronic infections within the particular context of a male-to-male transmission cluster. DESIGN: We compared the genotypic and phenotypic properties of envelope glycoproteins from viral variants derived from five study participants from the same transmission cluster. METHODS: We used single-genome amplification to generate a collection of full-length env sequences. We then constructed pseudotyped viruses expressing selected Env variants from the quasispecies infecting each study participant and compared their infectivities and sensitivities to various entry inhibitors. RESULTS: The genotypic analyses confirmed the genetic bottleneck expected after HIV transmission, with a limited number of variants identified in four study participants during acute infection. However, the transmitted sequences harbored no evident common signature and belonged to various genetic lineages. The phenotypic analyses revealed no difference in infectivity, susceptibility to the CCR5 antagonist maraviroc, the fusion inhibitor enfurvitide or type-I interferon between viruses from participants with acute and chronic infections. The key property distinguishing transmitted viruses was a higher resistance to soluble CD4, correlated with greater sensitivity to occupation of the CD4 receptor by the anti-CD4 antibodies LM52 and SK3. CONCLUSION: These results suggest that envelope glycoproteins from transmitted/founder viruses bind CD4 less efficiently than those of viruses from chronic infections.

Common evolutionary features of the envelope glycoprotein of HIV-1 in patients belonging to a transmission chain.

The diversity of the HIV-1 envelope glycoproteins (Env) is largely a consequence of the pressure exerted by the adaptive immune response to infection. While it was generally assumed that the neutralizing antibody (NAb) response depended mainly on the infected individual, the concept that virus-related factors could be important in inducing this response has recently emerged. Here, we analyzed the influence of the infecting viral strain in shaping NAb responses in four HIV-1 infected subjects belonging to a transmission chain. We also explored the impact of NAb responses on the functional evolution of the viral quasispecies. The four patients developed a strong autologous neutralizing antibody response that drove viral escape and coincided with a parallel evolution of their infecting quasispecies towards increasing infectious properties, increasing susceptibility to T20 and increasing resistance to both CD4 analogs and V3 loop-directed NAbs. This evolution was associated with identical Env sequence changes at several positions in the V3 loop, the fusion peptide and the HR2 domain of gp41. The common evolutionary pattern of Env in different hosts suggests that the capacity of a given Env to adapt to changing environments may be restricted by functional constraints that limit its evolutionary landscape.

Anticardiolipin antibodies in HIV infection are independently associated with antibodies to the membrane proximal external region of gp41 and with cell-associated HIV DNA and immune activation.

BACKGROUND: The demonstration of in vitro cardiolipin reactivity with 2 human immunodeficiency virus (HIV)-specific, broadly neutralizing antibodies (2F5 and 4E10) has prompted reevaluation of autoimmune manifestations in HIV infection. METHODS: We evaluated autoantibodies, particularly anticardiolipin (aCL), in 67 untreated, asymptomatic, HIV-infected individuals with slow progression of HIV disease and their correlation with 2F5-, 4E10-, b12-, and 2G12-like antibodies directed against epitopes involved in broad neutralization, as well as their correlation with immune activation and virological and clinical indicators. Fifty individuals with chronic HIV infection and standard disease progression were control patients. RESULTS: The majority of the study patients with slow progression of HIV disease were men (78%); their median age was 37 years, their median CD4+ cell count was 672 cells/mL, and their median plasma HIV load was 6200 copies/mL. The majority of the control patients were also men (76%), and most (62%) were receiving highly active antiretroviral therapy; their median age was 43 years, their median CD4+ cell count was 202 cells/mL, and their median plasma HIV load was 2265 copies/mL. aCL immunoglobulin G was detected at similar levels in 49% of patients with slow progression of HIV disease and in 58% of control patients. Viral load was positively associated with aCL in both groups (P < .001), independent of CD4+ cell counts. In patients with slow progression of HIV disease, aCL levels were also correlated with plasma HIV load and cell-associated DNA level (r = 0.486 and r = 0.516, respectively; P < .001), with the proportion of activated CD4+ cells, human leukocyte antigen-DR+ cells (r = 0.445; P = or < .001) but not activated CD8+ T cells, and with the level of B cell activation (quantified by soluble CD23; r = 0.354; P = .007). The level of aCL antibodies was associated with the level of antibodies to the membrane proximal region of gp41 (P = .003). CONCLUSION: aCL is frequently detected in HIV-infected patients, regardless of disease stage, and is strongly linked with the level of viral replication, the level of CD4+ T and B cell activation, and the level of antibodies to the membrane proximal external region of gp41, independent of CD4+ cell deficiency.

HIV-1 antibodies in prevention of transmission.

PURPOSE OF REVIEW: To present the data that suggest that antibodies to HIV may prevent HIV-1 infection. RECENT FINDINGS: Many human monoclonal broadly neutralizing antibodies (bnAbs) have been isolated over the last decade. Numerous experiments of passive immunization in nonhuman primate models have allowed to accumulate strong evidences that bnAbs, opposed to nonneutralizing antibodies, are the best candidates to prevent HIV-1 infection. bnAbs counteract HIV-1 by both blocking the virus at the portal of entry and clearing rapidly viral foci established at distance after dissemination of the virus following infection. Cocktails of bnAbs or modified bi/trispecific antibodies will be necessary to counter the large and evolving antigenic diversity of the HIV-1 species. Two large multicenter phase IIb clinical trials have been initiated. Even if they are not conducted with the most recent and most potent bnAb, the results which are expected in 2022 will inform us on the real potency of bnAbs at preventing HIV-1 acquisition in the real life. SUMMARY: If these trials demonstrate the efficacy of bnAbs, they will open the trail toward new strategies for preexposure prophylaxis, eventually postexposure prophylaxis and prevention of mother-to-child transmission.

Impact of HIV-1 Diversity on Its Sensitivity to Neutralization.

The HIV-1 pandemic remains a major burden on global public health and a vaccine to prevent HIV-1 infection is highly desirable but has not yet been developed. Among the many roadblocks to achieve this goal, the high antigenic diversity of the HIV-1 envelope protein (Env) is one of the most important and challenging to overcome. The recent development of broadly neutralizing antibodies has considerably improved our knowledge on Env structure and its interplay with neutralizing antibodies. This review aims at highlighting how the genetic diversity of HIV-1 thwarts current, and possibly future, vaccine developments. We will focus on the impact of HIV-1 Env diversification on the sensitivity to neutralizing antibodies and the repercussions of this continuous process at a population level.

Phenotypic properties of envelope glycoproteins of transmitted HIV-1 variants from patients belonging to transmission chains.

OBJECTIVE: Transmission of HIV-1 involves a bottleneck in which generally a single HIV-1 variant from a diverse viral population in the transmitting partner establishes infection in the new host. It is still unclear to what extent this event is driven by specific properties of the transmitted viruses or the result of a stochastic process. Our study aimed to better characterize this phenomenon and define properties shared by transmitted viruses. DESIGN: We compared antigenic and functional properties of envelope glycoproteins of viral variants found during primary infection in 27 patients belonging to eight transmission chains. METHODS: We generated pseudotyped viruses expressing Env variants of the viral quasispecies infecting each patient and compared their sensitivity to neutralization by eight human monoclonal broadly neutralizing antibodies (HuMoNAbs). We also compared their infectious properties by measuring their infectivity and sensitivity to various entry inhibitors. RESULTS: Transmitted viruses from the same transmission chain shared many properties, including similar neutralization profiles, sensitivity to inhibitors, and infectivity, providing evidence that the transmission bottleneck is mainly nonstochastic. Transmitted viruses were CCR5-tropic, sensitive to MVC, and resistant to soluble forms of CD4, irrespective of the cluster to which they belonged. They were also sensitive to HuMoNAbs that target V3, the CD4-binding site, and the MPER region, suggesting that the loss of these epitopes may compromise their capacity to be transmitted. CONCLUSION: Our data suggest that the transmission bottleneck is governed by selective forces. How these forces confer an advantage to the transmitted virus has yet to be determined.