Short Communication: HIV Type 1 Subtype C Variants Transmitted Through the Bottleneck of Breastfeeding Are Sensitive to New Generation Broadly Neutralizing Antibodies Directed Against Quaternary and CD4-Binding Site Epitopes

Abstract

Mother-to-child transmission of HIV-1 subtype C can occur in utero, intrapartum, or via breast milk exposure. While not well understood, there are putative differences in the mechanisms involved with the distinct routes of vertical HIV transmission. Here, we address the question of whether specific viral characteristics are common to variants transmitted through breastfeeding that may facilitate evasion of innate or adaptive immune responses. We amplified the envelope gene (env) from the plasma of six infants during acute infection who were infected with HIV-1 subtype C through breastfeeding, and from three available matched maternal samples. We sequenced the full-length env genes in these subjects revealing heterogeneous viral populations in the mothers and homogeneous populations in the infants. In five infants, the viral population arose from a single variant, while two variants were detected in the remaining infant. Infant env sequences had fewer N-linked glycosylation sites and shorter sequences than those of the available matched maternal samples. Though the small size of the study precluded our ability to test statistical significance, these results are consistent with selection for virus with shorter variable loops and fewer glycosylation sites during transmission of HIV-1 subtype C in other settings. Transmitted envs were resistant to neutralization by antibodies 2G12 and 2F5, but were generally sensitive to the more broadly neutralizing PG9, PG16, and VRC01, indicating that this new generation of broadly neutralizing monoclonal antibodies could be efficacious in passive immunization strategies.T ransmission of human immunodeficiency virus-1 (HIV-1) through breastfeeding (BF) makes up one-third to one-half of all mother-to-child transmission events.1 The mechanism(s) of transmission, however, are poorly understood. The oral cavity and gastrointestinal tract of breastfed infants are exposed daily to both cell-free and cell-associated HIV-1, 2-4 yet the majority of infants remain uninfected even if neither mother nor baby receive antiretroviral prophylaxis. 5This inefficiency of transmission indicates that anatomical, innate, and/or adaptive mechanisms of protection are able to prevent transmission to a great extent.6-11 Maternal antibodies could prevent infection either through direct binding of virus in the breast milk, or by their systemic and mucosal presence in the infant. This passive maternal immunity in the infant increases in concentration during the last trimester of gestation, and continues to pass into the infant through breastfeeding.Studies of in utero and intrapartum transmission have shown a universal bottleneck in genetic diversity from mother to child, as well as differences in the characteristics of transmitted virus for in utero versus intrapartum transmission. 12,13 Data are very limited for breastfeeding pairs, but one study of three breast milk transmission events found a similar bottleneck for HIV-1 subtype A.14 We previously demonstrated that the viral population found in ...

The oral mucosa immune environment and oral transmission of HIV/SIV

“…Higher SIV dose substantially increases the number of founder variants in macaque studies (93, 139–141), and a similar phenomenon has been observed in infants whose mothers seroconvert during breastfeeding (138, 142), likely due to high breast milk viral loads during acute infection. Also, similar to other routes of infection, only CCR5-tropic HIV viral variants establish infection in vivo (137, 142). Consistent with this observation, only macrophages infected with CCR5-tropic virus can migrate through infant oral mucosa to gain access to the HIV target cells of the lamina propria (108).…”

Computational analysis of antibody dynamics identifies recent HIV-1 infection

“…The humoral response to HIV-1 infection is marked by the dynamic appearance and disappearance of certain antibody isotypes and subclasses to different viral antigens from acute to longstanding infection. To harness this information for an HIV-1 incidence assay, we tested different antibody forms (i.e., IgM, IgG, IgG3, IgG4, IgA) in concert with a wide variety of HIV-1 antigens (i.e., peptides and proteins derived from env, gag, pol genes) to comprehensively cover the epitopes and antigen structures most likely to be reactive with immune sera from recent to chronic infection, including transmitted/ founder envelope (T/F) proteins (22)(23)(24)(25)(26). The analysis includes the presence or absence of the response along with the magnitude and avidity of the antibody response when present.…”

Clonal amplification and maternal-infant transmission of nevirapine-resistant HIV-1 variants in breast milk following single-dose nevirapine prophylaxis

“…Studies that have proposed transmission of wild-type virus followed by selection of resistant variants that were only detectable by sensitive assays based their interpretation on the timing of infection and likely exposure to NVP [10,11,23]. A similar interpretation should follow when population sequencing shows mixed wild-type and resistant viruses, unless both forms were simultaneously transmitted; a scenario less likely given the genetic bottleneck of MTCT of HIV [24,25] and the fact that most (~80%) HIV infections in heterosexuals [18,26] and infants via breast milk [27] result from transmission of a single virus. Thus, our study is important in that it establishes the NVP-R breast milk virus population selected by maternal sdNVP as the origin of the NVP-R virus in this postnatally-infected infant.…”