Relative resistance of patient-derived envelope sequences to SERINC5-mediated restriction of HIV-1 infectivity

A host cellular transmembrane protein, SERINC5, inhibits HIV-1 infectivity when incorporated into progeny virions. Recent studies suggest that certain Envelope glycoproteins can resist SERINC5-mediated restriction. However, the underlying mechanism of Envelope glycoprotein-mediated resistance to SERINC5 restriction remains unclear. Here, we investigated the extent of sensitivity of patient-derived HIV-1 Envelope sequences to SERINC5-mediated restriction and examined Envelopes' characteristics in relation to SERINC5. A nef-deficient HIV-1 reporter was pseudotyped with Envelope sequences isolated from a total of 50 Tanzanians infected with non-B HIV-1 subtypes in the presence and absence of SERINC5 expression. The infectivity of resultant pseudoviruses was differentially reduced by SERINC5 by a median of 5.1-fold (IQR: 3.2-8.6) including five outliers showing >= 20-fold reduction, whereas the pseudovirus with the control NL4-3 envelope was reduced by 64-fold. The pseudovirus sensitivity to SERINC5-mediated restriction differed significantly among the subtypes of the envelope sequences but was not associated with any other Envelope characteristics or clinical parameters tested. Within some hosts, the pseudovirus sensitivity to SERINC5 varied substantially among Envelope sequences, with sensitive ones (as defined by >= 20-fold reduction) being underrepresented. Analysis of chimeric constructs between intra-host clones revealed that both N- and C-terminus of the Envelope sequences were responsible for SERINC5-mediated restriction. Taken together, these results demonstrate that the majority of naturally occurring Envelope sequences across multiple subtypes are relatively less sensitive to SERINC5-mediated restriction of infectivity and that naturally occurring polymorphisms at N- and C-terminal parts are important for this sensitivity. IMPORTANCE Pathogenesis of HIV-1 is enhanced through several viral-encoded proteins that counteract a range of host restriction molecules. HIV-1 Nef counteracts the cell membrane protein SERINC5 by downregulating it from the cell surface, thereby enhancing virion infectivity. Some subtype B reference Envelope sequences have shown the ability to bypass SERINC5 infectivity restriction independent of Nef. However, it is not clear if and to what extent circulating HIV-1 strains can exhibit resistance to SERINC5 restriction. Using a panel of Envelope sequences isolated from 50 Tanzanians infected with non-B HIV-1 subtypes, we show that the lentiviral reporters pseudotyped with patient-derived Envelopes have reduced sensitivity to SERINC5 and that this sensitivity differed among viral subtypes. Moreover, we found that SERINC5 sensitivity within patient-derived Envelopes can be modulated by separate regions, highlighting the complexity of viral/host interactions.