Differential Pressures of SERINC5 and IFITM3 on HIV-1 Envelope Glycoprotein over the Course of HIV-1 Infection

Abstract

Infection of human immunodeficiency virus type 1 (HIV-1) is subject to restriction by cellular factors. Serine incorporator 5 (SERINC5) and interferon inducible transmembrane 3 (IFITM3) proteins represent two of these restriction factors, which inhibit HIV-1 entry into target cells. Both proteins impede fusion of the viral membrane with the cellular membrane and the formation of a viral fusion pore, and both are countered by the HIV-1 envelope glycoprotein (Env). Given the immense and lasting pressure which Env endures from host adaptive immune responses, it is important to understand whether and how HIV-1 Env is able to maintain the resistance to SERINC5 and IFITM3 throughout the course of infection. We have thus examined a panel of HIV-1 Env clones that were isolated at different stages of viral infection: transmission, acute and chronic. While HIV-1 Env clones from the transmission stage are resistant to both SERINC5 and IFITM3, as infection progresses into the acute and chronic stages, the resistance to IFITM3 but not to SERINC5 is gradually lost. We further discovered a significant correlation between the resistance of HIV-1 Env to soluble CD4 inhibition and the resistance to SERINC5 but not to IFITM3. Interestingly, the miniprotein CD4 mimetic M48U1 sensitizes HIV-1 Env to the inhibition by SERINC5 but not IFITM3. Together, these data indicate that SERINC5 and IFITM3 exert differential inhibitory pressures on HIV-1 Env over different stages of HIV-1 infection, and that HIV-1 Env uses varied strategies to resist these two restriction factors. IMPORTANCE HIV-1 Env protein is exposed to the inhibition not only by humoral response, but also by host restriction factors, including SERINC5 and IFITM3. This study investigates how HIV-1 Env manages to overcome the pressures from all these different host inhibition mechanisms over the long course of viral infection. While HIV-1 Env preserves the resistance to SERINC5, but becomes sensitive to IFITM3 when infection progresses into the chronic stage. Our study also supports the possibility of using CD4 mimetic compounds to sensitize HIV-1 Env to the inhibition by SERINC5, as a potential therapeutic strategy.

Coelacanth SERINC2 Inhibits HIV-1 Infectivity and Is Counteracted by Envelope Glycoprotein from Foamy Virus

“…The FV envelope’s ability to engage the endolysosomal machinery of the host to selectively target coelacanth SERINC 2, but not human SERINC2 and SERINC5 , for degradation in a heterologous host is impressive, as was the case with other retroviral factors ( 53 , 54 ). The counteraction phenotype associated with the FV envelope demonstrated here is also in agreement with the ability of SERINC 5 to restrict the virus in an envelope-dependent manner ( 20 , 21 , 25 , 31 , 55 , 56 ), indicating the envelope as a determinant for SERINC sensitivity to particle restriction. Therefore, the finding of FV envelope-dependent activity against coelacanth SERINC2 is in agreement with previous reports ( 55 , 56 ).…”

“…SERINC s plausibly shaped retroviral evolution, as indicated by the parallel emergence of anti- SERINC 5 activity among diverse retroviral genomes ( 18 , 23 , 31 , 32 ). Since the SERINC gene family is conserved across eukaryotic species, we investigated the extent to which the ability of SERINC orthologs to restrict HIV-1 is conserved.…”

Membrane Interference Against HIV-1 by Intrinsic Antiviral Factors: The Case of IFITMs

“…These strains exhibit unique features when compared to isolates derived from the chronic phase and in particular, a higher resistance to type I interferons (IFN-I) that can be partly ascribed to IFITM-resistance [ 44 , 74 ]. The major viral genetic determinant of this resistance has been mapped to the envelope glycoprotein [ 34 , 44 , 75 , 76 ] and specifically to several variable loops present in gp120: V3, the first identified, as well as V1 and V2 identified more recently [ 73 ].…”

“…In general, HIV-1 strains most affected by IFITMs present envelopes with lower gp120/gp41 association indexes and are more easily neutralized by soluble CD4 [ 75 ]. Such envelopes are hypothesized to sample more frequently open conformations and to display higher energetic state and lower conformational stability [ 73 , 76 ] that IFITMs can further exacerbate. It is of interest that lab-adapted strains susceptible to IFITMs are X4-tropic, while resistant ones are R5-tropic and that the V3 loop that confers resistance to IFITMs specifies R5-tropism and contains less polar residues that are thought to promote close envelope conformations.…”

Retroviral Restriction Factors and Their Viral Targets: Restriction Strategies and Evolutionary Adaptations

“…SERINC5-mediated restriction of HIV-1 is virus Env-type dependent, suggesting that SERINC5 restriction could be at the level of viral entry ( Figure 1 ) [ 36 , 37 , 48 , 49 ]. In accordance with this finding, viral reverse transcription in target cells is reduced and viral core delivery to the cytoplasm is blocked in the presence of SERINC5 [ 36 , 37 , 50 ].…”