Although both C-C chemokine receptor 5 (CCR5)- and CXC chemokine receptor 4 (CXCR4)-using HIV-1 strains cause AIDS, the emergence of CXCR4-utilizing variants is associated with an accelerated decline in CD4 + T cells. It remains uncertain if CXCR4-using viruses hasten disease or if these variants only emerge after profound immunological damage. We show that exclusively CXCR4- as compared to cocirculating CCR5-utilizing variants are less sensitive to neutralization by both contemporaneous autologous plasma and plasma pools from individuals that harbor only CCR5-using HIV-1. The CXCR4-utilizing variants, however, do not have a global antigenic change because they remain equivalently susceptible to antibodies that do not target coreceptor binding domains. Studies with envelope V3 loop directed antibodies and chimeric envelopes suggest that the neutralization susceptibility differences are potentially influenced by the V3 loop. In vitro passage of a neutralization sensitive CCR5-using virus in the presence of autologous plasma and activated CD4 + T cells led to the emergence of a CXCR4-utilizing virus in 1 of 3 cases. These results suggest that in some but not necessarily all HIV-1 infected individuals humoral immune pressure against the autologous virus selects for CXCR4-using variants, which potentially accelerates disease progression. Our observations have implications for using antibodies for HIV-1 immune therapy.

In clinical trials, HIV-1 broadly neutralizing antibodies (bnAbs) effectively lower plasma viremia and delay virus reemergence. The presence of less neutralization-susceptible strains prior to treatment decreases the efficacy of these antibody-based treatments, but neutralization sensitivity often cannot be predicted by sequence analysis alone. We found that phenotypically confirmed CXCR4-utilizing strains are less neutralization sensitive, especially to variable loop 3 (V3 loop)-directed bnAbs, than exclusively CCR5-utilizing strains in some, but not all, cases. Homology modeling suggested that the primary V3 loop bnAb epitope is equally accessible among CCR5- and CXCR4-using strains, although variants that exclusively use CXCR4 have V3 loop protrusions that interfere with CCR5 receptor interactions. Homology modeling also showed that among some, but not all, envelopes with decreased neutralization sensitivity, V1 loop orientation interfered with V3 loop-directed bnAb binding. Thus, there are likely different structural reasons for the coreceptor usage restriction and the different bnAb susceptibilities. Importantly, we show that individuals harboring envelopes with higher likelihood of using CXCR4 or greater predicted V1 loop interference have faster virus rebound and a lower maximum decrease in plasma viremia, respectively, after treatment with a V3 loop bnAb. Knowledge of receptor usage and homology models may be useful in developing future algorithms that predict treatment efficacy with V3 loop bnAbs. IMPORTANCE The efficacy of HIV-1 broadly neutralizing antibody (bnAb) therapies may be compromised by the preexistence of less susceptible variants. Sequence-based methods are needed to predict pretreatment variants’ neutralization sensitivities. HIV-1 strains that exclusively use the CXCR4 receptor rather than the CCR5 receptor are less neutralization susceptible, especially to variable loop 3 (V3 loop) bnAbs in some, but not all, instances. While the inability to utilize the CCR5 receptor maps to a predicted protrusion in the envelope V3 loop, this viral determinant does not directly influence V3 loop bnAb sensitivity. Homology modeling predicts that contact between the envelope V1 loop and the antibody impacts V3 loop bnAb susceptibility in some cases. Among pretreatment envelopes, increased probability of using CXCR4 and greater predicted V1 interference are associated with faster virus rebound and a smaller decrease in the plasma virus level, respectively, after V3 loop bnAb treatment. Receptor usage information and homology models may be useful for predicting V3 loop bnAb therapy efficacy.

16In clinical trials, HIV-1 broadly neutralizing antibodies (bnAbs) effectively lower plasma viremia 17 and delay virus reemergence after antiretroviral treatment is stopped among infected individuals 18 that have undetectable virus levels. Presence of less neutralization susceptible strains prior to 19 treatment, however, decreases the efficacy of these antibody-based treatments. The HIV-1 20 envelope glycoprotein harbors extensive genetic variation, and thus, neutralization sensitivity 21 often cannot be predicted by sequence analysis alone. Sequence-based prediction methods are 22 neutralization resistant [17][18][19]. We compared the eleven R5 only and seven DM plasma's 126 neutralization capacity against Envs in the reference global panel (all R5) to those in the 127 CXCR4-using collection to provide further generalizability for this conclusion. The eighteen 128 plasma had decreased neutralization capacity (around 1.5 fold lower BP score) against the 129 CXCR4-using as compared to against the global reference Env panel (p = 0.01) ( Fig 1G). 130Furthermore, neutralization breadth was significantly lower against the CXCR4-using as 131 compared to the global reference Env collection (p = 0.02) ( Fig 1H). These observations 132 suggest that, in general, HIV-1B CXCR4-as compared to CCR5-using viruses are more

The discovery of a new generation of highly potent broadly neutralising antibodies (bnAb) has provided a new weapon in the fight against HIV-1. It is envisioned that multiple bnAb or a single bnAb in conjunction with antiretrovirals (ARV) can be used to treat HIV infection, especially individuals harbouring extensively drug-resistant virus or those that require regimen simplification. Furthermore, it is believed that bnAb may eliminate latently infected cells through antibody-mediated cellular cytotoxicity, and this functionality may induce virus remission. BnAb epitopes and HIV envelope determinants for CCR5 and CXCR4 usage often overlap, and this provides the basis for believing that there is a relationship between receptor utilisation and bnAb sensitivity. This review highlights the important intersection between HIV co-receptor usage and bnAb therapy. Compared to CCR5-using strains, CXCR4 strains are generally more resistant to bnAb that target the V1-V2 apex and V3 N332 glycan, but not the other envelope domains. This association between bnAb sensitivity and co-receptor usage can be leveraged both to develop pre-treatment assays to identify resistant strains, as well as to anticipate potential adverse outcomes with future HIV antibody-based therapeutics.