Phenotypic and Immunologic Comparison of Clade B Transmitted/Founder and Chronic HIV-1 Envelope Glycoproteins

Wilen, Craig B.; Parrish, Nicholas F.; Pfaff, Jennifer M.; Decker, Julie M.; Henning, Elizabeth A.; Haim, Hillel; Petersen, Josiah; Wojcechowskyj, Jason A.; Sodroski, Joseph; Haynes, Barton F.; Montefiori, David C.; Tilton, John C.; Shaw, George M.; Hahn, Beatrice H.; Doms, Robert W.

doi:10.1128/jvi.00736-11

Cited by 112 publications

(155 citation statements)

References 80 publications

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“…In this context, it is critical to know whether transmitted viruses possess unique biological properties that predispose them to establish new infections more efficiently. This is a controversial topic, because some studies have reported TF-specific traits (22,24,26,52,(55)(56)(57), whereas others have failed to confirm these results (27,28,53,58,59). Some of these discrepancies are likely due to the fact that most previous analyses did not compare HIV-1 strains from transmission pairs.…”

Section: Discussionmentioning

confidence: 54%

“…in activated CD4 + T cells but not macrophages (14,(22)(23)(24)(25). Moreover, analysis of a comprehensive panel of infectious molecular clones (IMCs) showed that TF viruses packaged more envelope glycoprotein (Env), exhibited greater infectivity, bound to monocyte-derived dendritic cells more efficiently, and replicated to higher titers in CD4 + T cells in the presence of the type 1 interferon IFNα2 than chronic control (CC) viruses (26).…”

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confidence: 99%

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Resistance to type 1 interferons is a major determinant of HIV-1 transmission fitness

Iyer

Bibollet-Ruche

Sherrill-Mix

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Sexual transmission of HIV-1 is an inefficient process, with only one or few variants of the donor quasispecies establishing the new infection. A critical, and as yet unresolved, question is whether the mucosal bottleneck selects for viruses with increased transmission fitness. Here, we characterized 300 limiting dilution-derived virus isolates from the plasma, and in some instances genital secretions, of eight HIV-1 donor and recipient pairs. Although there were no differences in the amount of virion-associated envelope glycoprotein, recipient isolates were on average threefold more infectious (P = 0.0001), replicated to 1.4-fold higher titers (P = 0.004), were released from infected cells 4.2-fold more efficiently (P < 0.00001), and were significantly more resistant to type I IFNs than the corresponding donor isolates. Remarkably, transmitted viruses exhibited 7.8-fold higher IFNα2 (P < 0.00001) and 39-fold higher IFNβ (P < 0.00001) half-maximal inhibitory concentrations (IC 50 ) than did donor isolates, and their odds of replicating in CD4 + T cells at the highest IFNα2 and IFNβ doses were 35-fold (P < 0.00001) and 250-fold (P < 0.00001) greater, respectively. Interestingly, pretreatment of CD4 + T cells with IFNβ, but not IFNα2, selected donor plasma isolates that exhibited a transmitted virus-like phenotype, and such viruses were also detected in the donor genital tract. These data indicate that transmitted viruses are phenotypically distinct, and that increased IFN resistance represents their most distinguishing property. Thus, the mucosal bottleneck selects for viruses that are able to replicate and spread efficiently in the face of a potent innate immune response.

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Section: Discussionmentioning

confidence: 54%

mentioning

confidence: 99%

Resistance to type 1 interferons is a major determinant of HIV-1 transmission fitness

Iyer

Bibollet-Ruche

Sherrill-Mix

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

132

180

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“…This has made it possible to seek genotypic and phenotypic differences between T/F Env proteins and those derived from chronically infected individuals (chronic control [CC] Envs). Several phenotypic characteristics are clearly associated with transmission: T/F Envs virtually always use CCR5 rather than CXCR4 or other noncanonical coreceptors (2,(16)(17)(18) and generally infect T cells but not macrophages (2,13,15,19) as a result of requiring relatively high levels of CD4 to mediate virus entry (20)(21)(22)(23)(24)(25). Other phenotypic and genotypic traits that have been linked to transmission are less well defined: Envs isolated from acute infection have sometimes been reported to be more neutralization sensitive (19), have on average fewer putative N-linked glycosylation sites (1,26), and have shorter variable loops (1,(27)(28)(29) compared to Envs isolated from chronically infected individuals.…”

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confidence: 99%

Transmitted/Founder and Chronic HIV-1 Envelope Proteins Are Distinguished by Differential Utilization of CCR5

Parker

Iyer

Wilen

et al. 2013

J Virol

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“…This is relevant because, at least for clade B, there is evidence that sequences from individuals with acute HIV infection are more sensitive to VRC01-mediated neutralization than those from individuals with chronic HIV infection. 23 Moreover, the model does not account for the fact that AMP participants are exposed to HIV-1 quasispecies and VRC01 may need to neutralize all resistant variants or at least all resistant variants of some unknown minimum prevalence in the quasispecies. 26 Our sensitivity analyses in Figure 6 address the possibility that AMP participants are exposed to viruses (or virus variants) more resistant to VRC01-mediated neutralization than those in the panel.…”

Section: Discussionmentioning

confidence: 99%

Modeling cumulative overall prevention efficacy for the VRC01 phase 2b efficacy trials

Huang

Karuna

Carpp

et al. 2018

Human Vaccines & Immunotherapeutics

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The Antibody Mediated Prevention trials are assessing whether intravenously-administered VRC01 (10 mg/kg or 30 mg/kg vs placebo) can prevent HIV infection. In a modeling exercise, we used two models to predict the overall prevention efficacy (PE) of each VRC01 dose in preventing HIV infection. For the first per-exposure PE model, parameters were estimated from studies where nonhuman primates (NHPs) were administered high-dose intra-rectal simian-human immunodeficiency virus challenge two days post-VRC01 infusion at various dosages (“NHP model”). To account for the fact that humans may require greater VRC01 concentration to achieve the same level of protection, we next assumed that a 5-fold greater VRC01 serum concentration would be needed to provide the same level of per-exposure PE as seen in the NHP data (“5-fold model”). For the 10 mg/kg regimen, the 5-fold and NHP models predict an overall PE of 37% and 64%, respectively; for the 30 mg/kg regimen, the two models predict an overall PE of 53% and 82%, respectively. Our results support that VRC01 may plausibly confer positive PE in the AMP trials. Given the lack of available knowledge and data to verify the assumptions undergirding our modeling framework, its quantitative predictions of overall PE are preliminary. Its current main applications are to supplement decisions to advance mAb regimens to efficacy trials, and to enable mAb regimen ranking by their potential for PE in humans.

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Phenotypic and Immunologic Comparison of Clade B Transmitted/Founder and Chronic HIV-1 Envelope Glycoproteins

Cited by 112 publications

References 80 publications

Resistance to type 1 interferons is a major determinant of HIV-1 transmission fitness

Resistance to type 1 interferons is a major determinant of HIV-1 transmission fitness

Transmitted/Founder and Chronic HIV-1 Envelope Proteins Are Distinguished by Differential Utilization of CCR5

Modeling cumulative overall prevention efficacy for the VRC01 phase 2b efficacy trials

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