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

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

doi:10.1186/s12977-019-0510-1

Hanwei Sudderuddin, Rachel L Miller + Show 7 more

Open Access

https://doi.org/10.1186/s12977-019-0510-1

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Abstract

The HIV accessory protein Nef downregulates the viral entry receptor CD4, the Human Leukocyte Antigen (HLA)-A and -B molecules, the Serine incorporator 5 (SERINC5) protein and other molecules from the infected cell surface, thereby promoting viral infectivity, replication and immune evasion. The nef locus also represents one of the most genetically variable regions in the HIV genome, and nef sequences undergo substantial evolution within a single individual over the course of infection. Few studies however have simultaneously characterized the impact of within-host nef sequence evolution on Nef protein function over prolonged timescales. Here, we isolated 50 unique Nef clones by single-genome amplification over an 11-year period from the plasma of an individual who was largely naïve to antiretroviral treatment during this time. Together, these clones harbored nonsynonymous substitutions at 13% of nef’s codons. We assessed their ability to downregulate cell-surface CD4, HLA and SERINC5 and observed that all three Nef functions declined modestly over time, where the reductions in CD4 and HLA downregulation (an average of 0.6% and 2.0% per year, respectively) achieved statistical significance. The results from this case study support all three Nef activities as being important to maintain throughout untreated HIV infection, but nevertheless suggest that, despite nef’s mutational plasticity, within-host viral evolution can compromise Nef function, albeit modestly, over prolonged periods.

Highlights

HIV is an enveloped retrovirus with extensive capacity for mutation and within-host genetic diversification [1,2,3,4], which occur as a result of reverse transcriptase errors [5], viral recombination [6] and sublethal APOBEC3Gmediated mutagenesis [7] combined with a short viral generation time and high viremia during untreated infection [4]
Our study of within-host HIV nef function over an 11-year period revealed a number of insights
It confirmed marked within-host evolution in nef

Summary

Introduction

HIV is an enveloped retrovirus with extensive capacity for mutation and within-host genetic diversification [1,2,3,4], which occur as a result of reverse transcriptase errors [5], viral recombination [6] and sublethal APOBEC3Gmediated mutagenesis [7] combined with a short viral generation time and high viremia during untreated infection [4]. Of all the HIV genes, nef displays high rates of within-host viral diversification and evolution [16,17,18]. Nef is a determinant of HIV pathogenesis [19], and performs various functions that promote viral infectivity, replication and immune evasion [19,20,21]. Nef-mediated CD4 downregulation prevents cellular superinfection [25], allows infected cells. Nef-mediated HLA-A and -B downregulation allows HIV-infected cells to evade HLA-restricted CD8+ cytotoxic T lymphocyte (CTL) responses [29, 30]. Nef has been found to internalize the transmembrane host restriction factor Serine incorporator 5 (SERINC5), thereby preventing its inclusion into budding HIV virions and enhancing viral infectivity [31, 32]. We and others have observed that all three of these functions are attenuated in Nef clones isolated from HIV elite controllers who spontaneously suppress plasma viremia to < 50 RNA copies/mL in the absence of therapy [33,34,35,36,37], suggesting that variation in Nef activity contributes to biologic outcomes

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