Longitudinal within-host evolution of HIV Nef-mediated CD4, HLA and SERINC5 downregulation activity: a case study

Sudderuddin, Hanwei; Kinloch, Natalie N.; Jin, Steven; Miller, Rachel L.; Jones, Bradley R.; Brumme, Chanson J.; Joy, Jeffrey B.; Brockman, Mark A.; Brumme, Zabrina L.

doi:10.1186/s12977-019-0510-1

Cited by 11 publications

(13 citation statements)

References 73 publications

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“…We noticed that the chronic Env clones tend to be more resistant to SERINC5 than the T/F and acute Env clones. This may partly result from the accumulated polymorphisms in viral Nef protein over the long course of chronic infection, which impair the ability of Nef to counter SERINC5 (41). Partial loss of SERINC5 antagonism by Nef could lay more pressure on HIV-1 Env to resist SERINC5.…”

Section: Discussionmentioning

confidence: 99%

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

Beitari

Pan

Finzi

et al. 2020

J Virol

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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.

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Section: Discussionmentioning

confidence: 99%

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

Beitari

Pan

Finzi

et al. 2020

J Virol

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“…SERINC5-iHA expression was increased when JTAg-SERINC3/5 −/− cells were transfected with DNA encoding SERINC5-iHA, whereas co-transfection with DNA encoding SERINC5-iHA and Nef SF2 -GFP resulted in substantial reduction in cell surface expression of SERINC5-iHA ( Fig. 4A), confirming Nef 's ability to downregulate SERINC5 23,36,37 . All patient-derived Nef clones tested were functional with respect to the SERINC5-iHA downregulation function, but the activity level was different to a relatively small extent within a host, but to a large extent across hosts (Fig.…”

Section: Functional Effects Of Nef Variants In the Context Of Patientmentioning

confidence: 65%

Impaired ability of Nef to counteract SERINC5 is associated with reduced plasma viremia in HIV-infected individuals

Toyoda

Kamori

Tan

et al. 2020

Sci Rep

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HIV-1 Nef plays an essential role in enhancing virion infectivity by antagonizing the host restriction molecule SERINC5. Because Nef is highly polymorphic due to the selective forces of host cellular immunity, we hypothesized that certain immune-escape polymorphisms may impair Nef’s ability to antagonize SERINC5 and thereby influence viral fitness in vivo. To test this hypothesis, we identified 58 Nef polymorphisms that were overrepresented in HIV-infected patients in Japan sharing the same HLA genotypes. The number of immune-associated Nef polymorphisms was inversely correlated with the plasma viral load. By breaking down the specific HLA allele-associated mutations, we found that a number of the HLA-B*51:01-associated Y120F and Q125H mutations were most significantly associated with a reduced plasma viral load. A series of biochemical experiments showed that the double mutations Y120F/Q125H, but not either single mutation, impaired Nef’s ability to antagonize SERINC5 and was associated with decreasing virion infectivity and viral replication in primary lymphocytes. In contrast, other Nef functions such as CD4, CCR5, CXCR4 and HLA class I downregulation and CD74 upregulation remained unchanged. Taken together, our results suggest that the differential ability of Nef to counteract SERINC5 by naturally occurring immune-associated mutations was associated with the plasma viral load in vivo.

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“…Recent reports demonstrated that three specific sites in Nef, the amino acids 12 to 39, the ExxxLL motif (S163C) and the AP-2 binding site (R178G), were identified to be involved in Nef function [ 14 , 15 , 16 , 24 ] ( Figure 1 ). In addition, multiple amino acid variations in Nef (subtype B HIV-1) were identified to play a role in SERINC3 and SERINC5 antagonism [ 14 , 25 , 26 ] ( Figure 1 ) including 8R, 9S, 11P, 12G, 14A/P/S, 15A, 21K/R, 28E, 43I, N51T, 54D, 63E, 81F, H116N, 120F, V148L/X, 157N, 158K, 161N, M168I/X, 182E and 188S, of which some specifically affected SERINC3 (8R, 9S, 11P, 12G, 14A, 15A, 21K, 28E, 43I, 182E and 188S) or SERINC5 (14S, 21R, 54D, 63E, 81F, 120F, 157N and 158K) [ 26 ]. We analyzed primary Nef proteins obtained from 123 individuals with HIV-1 participating in the Amsterdam Cohort Studies for amino acid changes at the previously described positions and regions as compared to consensus B ( Supplementary Table S1 ).…”

Section: Resultsmentioning

confidence: 99%

Nef Obtained from Individuals with HIV-1 Vary in Their Ability to Antagonize SERINC3- and SERINC5-Mediated HIV-1 Restriction

Kruize

Nuenen

Wijk

et al. 2021

Viruses

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Nef is a multifunctional viral protein that has the ability to downregulate cell surface molecules, including CD4 and major histocompatibility complex class I (MHC-I) and, as recently shown, also members of the serine incorporator family (SERINC). Here, we analyzed the impact of naturally occurring mutations in HIV-1 Nef on its ability to counteract SERINC restriction and the clinical course of infection. HIV-1 Nef sequences were obtained from 123 participants of the Amsterdam Cohort Studies and showed multiple amino acid variations and mutations. Most of the primary Nef proteins showed increased activity to counteract SERINC3 and SERINC5 as compared to NL4-3 Nef. Several mutations in Nef were associated with either an increased or decreased infectivity of Bal26-pseudotyped HIV-1 produced in the presence of SERINC3 or SERINC5. The 8R, 157N and R178G Nef mutations were shown to have an effect on disease progression. Survival analysis showed an accelerated disease progression of individuals infected with HIV-1 carrying arginine or asparagine at position 8 or 157 in Nef, respectively, or the R178G Nef mutation. Here, we observed that naturally occurring mutations in Nef affect the ability of Nef to counteract SERINC3- and SERINC5-mediated inhibition of viral infectivity. The majority of these Nef mutations had no significant effect on HIV-1 pathogenesis and only the 8R, 157N and R178G mutations were associated with disease course.

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Longitudinal within-host evolution of HIV Nef-mediated CD4, HLA and SERINC5 downregulation activity: a case study

Cited by 11 publications

References 73 publications

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

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

Impaired ability of Nef to counteract SERINC5 is associated with reduced plasma viremia in HIV-infected individuals

Nef Obtained from Individuals with HIV-1 Vary in Their Ability to Antagonize SERINC3- and SERINC5-Mediated HIV-1 Restriction

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