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The HIV envelope (Env) is extensively modified with host-derived N-linked glycans. The high density of glycosylation on the viral spike limits enzymatic processing resulting in numerous under-processed oligomannose-type glycans. This extensive glycosylation not only shields conserved regions of the protein from the immune system but also act as targets for HIV broadly neutralizing antibodies (bnAbs). In response to the host immune system, the HIV glycan shield is constantly evolving through mutations affecting both the positions and frequencies of potential N-linked glycans (PNGSs). Here, using longitudinal Env sequences from a clade C infected individual (CAP256), we measure the impact of the shifting glycan shield during HIV infection on the abundance of oligomannose-type glycans. By analyzing the intrinsic mannose patch from a panel of recombinant CAP256 gp120s displaying high protein sequence variability and changes in PNGS frequency and positioning, we show that the intrinsic mannose-patch persists throughout the course of HIV infection and correlates with the number of PNGSs. This effect of glycan density on processing state was also supported by the analysis of a cross-clade panel of recombinant gp120 glycoproteins. Together, these observations underscore the importance of glycan clustering for the generation of carbohydrate epitopes for HIV bnAbs. The persistence of the intrinsic mannose patch over the course of HIV infection further highlights this epitope as an important target for HIV vaccine strategies.IMPORTANCE: Development of an HIV vaccine is critical for control of the HIV pandemic, and elicitation of broadly neutralizing antibodies (bnAbs), is likely to be a key component of a successful vaccine response. The HIV Envelope glycoprotein (Env) is covered in an array of host-derived N-linked glycans often referred to as the glycan shield. This glycan shield is a target for many of the recently isolated HIV bnAbs and is therefore under constant pressure from the host immune system leading to changes in both glycan site frequency and location. This study aimed to determine whether these genetic changes impacted the eventual processing of glycans on the HIV Env, and the viruses susceptibility to neutralization. We show that despite this variation in glycan site positioning and frequency over the course of HIV infection, the mannose patch is a conserved feature throughout, making it a stable target for HIV vaccine design.

Summary Interferon-induced transmembrane proteins (IFITMs) restrict the entry of diverse enveloped viruses through incompletely understood mechanisms. While IFITMs are reported to inhibit HIV-1, their in vivo relevance is unclear. We show that IFITM sensitivity of HIV-1 strains is determined by the co-receptor usage of the viral envelope glycoproteins as well as IFITM subcellular localization within the target cell. Importantly, we find that transmitted founder HIV-1, which establishes de novo infections, is uniquely resistant to the antiviral activity of IFITMs. However, viral sensitivity to IFITMs, particularly IFITM2 and IFITM3, increases over the first 6 months of infection, primarily as a result of neutralizing antibody escape mutations. Additionally, the ability to evade IFITM restriction contributes to the different interferon sensitivities of transmitted founder and chronic viruses. Together, these data indicate that IFITMs constitute an important barrier to HIV-1 transmission and that escape from adaptive immune responses exposes the virus to antiviral restriction., Graphical Abstract Image 1, Highlights • IFITM restriction of HIV-1 depends on virus co-receptor use and IFITM localization • Transmitted founder viruses are resistant to IFITM restriction • Escape from early neutralizing antibodies confers IFITM sensitivity • IFITM restriction contributes to the increased IFN sensitivity of chronic viruses, IFITMs are interferon-induced proteins with broad antiviral activity. Foster et al. demonstrate that HIV-1 sensitivity to IFITMs depends on the viral entry route into target cells. Strikingly, transmitted HIV-1 strains are IFITM resistant, but viral envelope mutations that escape neutralizing antibody responses after infection lead to IFITM and interferon sensitivity.