Sexual transmission of human immunodeficiency virus type 1 (HIV-1) most often results from productive infection by a single transmitted/founder (T/F) virus, indicating a stringent mucosal bottleneck. Understanding the viral traits that overcome this bottleneck could have important implications for HIV-1 vaccine design and other prevention strategies. Most T/F viruses use CCR5 to infect target cells and some encode envelope glycoproteins (Envs) that contain fewer potential N-linked glycosylation sites and shorter V1/V2 variable loops than Envs from chronic viruses. Moreover, it has been reported that the gp120 subunits of certain transmitted Envs bind to the gut-homing integrin α4β7, possibly enhancing virus entry and cell-to-cell spread. Here we sought to determine whether subtype C T/F viruses, which are responsible for the majority of new HIV-1 infections worldwide, share biological properties that increase their transmission fitness, including preferential α4β7 engagement. Using single genome amplification, we generated panels of both T/F (n = 20) and chronic (n = 20) Env constructs as well as full-length T/F (n = 6) and chronic (n = 4) infectious molecular clones (IMCs). We found that T/F and chronic control Envs were indistinguishable in the efficiency with which they used CD4 and CCR5. Both groups of Envs also exhibited the same CD4+ T cell subset tropism and showed similar sensitivity to neutralization by CD4 binding site (CD4bs) antibodies. Finally, saturating concentrations of anti-α4β7 antibodies failed to inhibit infection and replication of T/F as well as chronic control viruses, although the growth of the tissue culture-adapted strain SF162 was modestly impaired. These results indicate that the population bottleneck associated with mucosal HIV-1 acquisition is not due to the selection of T/F viruses that use α4β7, CD4 or CCR5 more efficiently. Most new HIV-1 infections worldwide are caused by the sexual transmission of subtype C viruses, which are prevalent in Asia and southern Africa. While chronically infected individuals harbor a genetically diverse set of viruses, most new infections are established by single variants, termed transmitted/founder (T/F) viruses. This raises the question whether certain viral variants have particular properties allowing them to more efficiently overcome the transmission bottleneck. Preferential binding of the viral envelope (Env) to the integrin α4β7 has been hypothesized as one important feature of transmitted viruses. Here, we compared Envs from subtype C viruses that were transmitted to those that were prevalent in chronic infections for efficiency in utilizing α4β7, CD4 and CCR5 for cell entry and replication. We found that transmitted and chronic Envs engaged CD4 and CCR5 with equal efficiency, and that blocking the interaction between Env and α4β7 failed to inhibit replication of T/F as well as control viruses. While the search for determinants of transmission fitness remains an important goal, preferential CD4, CCR5 or α4β7 interactions do not appear to represent distinguishing features of T/F viruses.

Growing evidence suggests that ABO blood group may play a role in the immunopathogenesis of SARS‐CoV‐2 infection, with group O individuals less likely to test positive and group A conferring a higher susceptibility to infection and propensity to severe disease. The level of evidence supporting an association between ABO type and SARS‐CoV‐2/COVID‐19 ranges from small observational studies, to genome‐wide‐association‐analyses and country‐level meta‐regression analyses. ABO blood group antigens are oligosaccharides expressed on red cells and other tissues (notably endothelium). There are several hypotheses to explain the differences in SARS‐CoV‐2 infection by ABO type. For example, anti‐A and/or anti‐B antibodies (e.g. present in group O individuals) could bind to corresponding antigens on the viral envelope and contribute to viral neutralization, thereby preventing target cell infection. The SARS‐CoV‐2 virus and SARS‐CoV spike (S) proteins may be bound by anti‐A isoagglutinins (e.g. present in group O and group B individuals), which may block interactions between virus and angiotensin‐converting‐enzyme‐2‐receptor, thereby preventing entry into lung epithelial cells. ABO type‐associated variations in angiotensin‐converting enzyme‐1 activity and levels of von Willebrand factor (VWF) and factor VIII could also influence adverse outcomes, notably in group A individuals who express high VWF levels. In conclusion, group O may be associated with a lower risk of SARS‐CoV‐2 infection and group A may be associated with a higher risk of SARS‐CoV‐2 infection along with severe disease. However, prospective and mechanistic studies are needed to verify several of the proposed associations. Based on the strength of available studies, there are insufficient data for guiding policy in this regard.

The development of biomedical interventions to reduce acquisition of HIV-1 infection remains a global priority, however their potential effectiveness is challenged by very high HIV-1 envelope diversity. Two large prophylactic trials in high incidence, clade C epidemic regions in southern Africa are imminent; passive administration of the monoclonal antibody VRC01, and active immunization with a clade C modified RV144-like vaccines. We have created a large representative panel of C clade viruses to enable assessment of antibody responses to vaccines and natural infection in Southern Africa, and we investigated the genotypic and neutralization properties of recently transmitted clade C viruses to determine how viral diversity impacted antibody recognition. We further explore the implications of these findings for the potential effectiveness of these trials. A panel of 200 HIV-1 Envelope pseudoviruses was constructed from clade C viruses collected within the first 100 days following infection. Viruses collected pre-seroconversion were significantly more resistant to serum neutralization compared to post-seroconversion viruses (p = 0.001). Over 13 years of the study as the epidemic matured, HIV-1 diversified (p = 0.0009) and became more neutralization resistant to monoclonal antibodies VRC01, PG9 and 4E10. When tested at therapeutic levels (10ug/ml), VRC01 only neutralized 80% of viruses in the panel, although it did exhibit potent neutralization activity against sensitive viruses (IC₅₀ titres of 0.42 μg/ml). The Gp120 amino acid similarity between the clade C panel and candidate C-clade vaccine protein boosts (Ce1086 and TV1) was 77%, which is 8% more distant than between CRF01_AE viruses and the RV144 CRF01_AE immunogen. Furthermore, two vaccine signature sites, K169 in V2 and I307 in V3, associated with reduced infection risk in RV144, occurred less frequently in clade C panel viruses than in CRF01_AE viruses from Thailand. Increased resistance of pre-seroconversion viruses and evidence of antigenic drift highlights the value of using panels of very recently transmitted viruses and suggests that interventions may need to be modified over time to track the changing epidemic. Furthermore, high divergence such as that observed in the older clade C epidemic in southern Africa may impact vaccine efficacy, although the correlates of infection risk are yet to be defined in the clade C setting. Findings from this study of acute/early clade C viruses will aid vaccine development, and enable identification of new broad and potent antibodies to combat the HIV-1 C-clade epidemic in southern Africa. Vaccine and passive immunization prophylactic trials that rely on antibody-mediated protection are planned for HIV-1 clade C epidemic regions of southern Africa, which have amongst the highest HIV-1 incidences globally. This includes a phase 2b trial of passively administered monoclonal antibody, VRC01; as well as a phase 3 trial using the clade C modified version of the partially efficacious RV144 vaccine. The extraordinary diversity of HIV-1 poses a major obstacle to these interventions, and our study aimed to determine the implications of viral diversity on antibody recognition. Investigations using our panel of very early viruses augment current knowledge of vulnerable targets on transmitted viruses for vaccine design and passive immunization studies. Evidence of antigenic drift with viruses becoming more resistant over time suggests that these prevention modalities will need to be updated over time and that combinations of antibodies will be necessary to achieve coverage in passive immunization studies. We further show that it may be more difficult to obtain protection in the genetically diverse clade C epidemic compared to RV144 where the epidemic is less diverse, although it should be noted that the correlates of infection risk are yet to be defined in the clade C setting.