Transmitted/founder (T/F) HIV-1 derived from sexual contact exhibits greater transmission fitness in human cervical tissue than T/F HIV-1 from blood-to-blood contact: Unique glycan profiles on T/F envelopes associated with transmission phenotypes.

Human immunodeficiency virus 1 (HIV-1) risk groups include, but are not limited to, heterosexual individuals (HET), men-who-have-sex-with-men (MSM), and people who inject drugs (PWID). Although genetically diverse HIV-1 populations are transferred from donor to recipient, systemic infection is often established by a single clone, the transmitted/founder (T/F) virus. This phenomenon is especially prevalent in sexual transmission, but less stringent in blood-to-blood contact transmission. Specific traits that permit successful transmission have not been well characterized. Thus, HIV-1 containing the chimeric T/F envelope (Env) from different transmission routes was assessed for ex vivo transmission fitness by performing mixed competition assays (also referred to as mixed competitions) on human cervical tissues. We found that chimeric T/F viruses isolated from the PWID exhibit limited replication capacity in cervical tissues when compared to those from MSM and HET, diminishing their chances of transmission to T helper type 1 (Th1) and Th17 cells. This reduced transmission fitness of T/F HIV-1 from PWID was not observed when infecting Th1 and Th17 cells directly, bypassing cervical tissues. Phenotypic assays showed that the chimeric T/F viruses from PWID differed from other groups by having an enhanced ability to utilize diverse CCR5 conformations, while Env expression level, CD4/CCR5 utilization, and entry speed did not differ. Different glycosylation profiles were detected on T/F compared to chronic Env with increased complex, fucosylated N- and O-glycans found more frequently on the T/F Env. Furthermore, the increased presence of these fucosylated glycans correlated with replication fitness in cervical tissues. In contrast, bisecting branched N-glycan found more frequently on chronic Env was associated with decreased entry efficiency and more stringent usage of CCR5. These findings suggest that glycosylation patterns/levels and/or Env structure greatly impact the differences in transmission fitness of T/F HIV-1.