P20-21 LB. Gene-to-gene differences in evolutionary rate between HIV-1 and natural SIV from sooty mangabeys: implications for vaccine tests in non-human primates

HIV-1 is a fast-evolving, genetically diverse virus presently classified into several groups and subtypes. The virus evolves rapidly because of an error-prone polymerase, high rates of recombination, and selection in response to the host immune system and clinical management of the infection. The rate of evolution is also influenced by the rate of virus spread in a population and nature of the outbreak, among other factors. HIV-1 evolution is thus driven by a range of complex genetic, social, and epidemiological factors that complicates disease management and prevention. Here, we quantify the evolutionary (substitution) rate heterogeneity among major HIV-1 subtypes and recombinants by analyzing the largest collection of HIV-1 genetic data spanning the widest possible geographical (100 countries) and temporal (1981–2019) spread. We show that HIV-1 substitution rates vary substantially, sometimes by several folds, both across the virus genome and between major subtypes and recombinants, but also within a subtype. Across subtypes, rates ranged 3.5-fold from 1.34 × 10−3 to 4.72 × 10−3 in env and 2.3-fold from 0.95 × 10−3 to 2.18 × 10−3 substitutions site−1 year−1 in pol. Within the subtype, 3-fold rate variation was observed in env in different human populations. It is possible that HIV-1 lineages in different parts of the world are operating under different selection pressures leading to substantial rate heterogeneity within and between subtypes. We further highlight how such rate heterogeneity can complicate HIV-1 phylodynamic studies, specifically, inferences on epidemiological linkage of transmission clusters based on genetic distance or phylogenetic data, and can mislead estimates about the timing of HIV-1 lineages.

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Site-Specific Evolutionary Rate Shifts in HIV-1 and SIV

Viruses ◽

10.3390/v12111312 ◽

2020 ◽

Vol 12 (11) ◽

pp. 1312

Author(s):

Maoz Gelbart ◽

Adi Stern

Keyword(s):

Evolutionary Rate ◽

Species Barrier ◽

Epistatic Interactions ◽

Site Specific ◽

Genome Wide ◽

Rate Acceleration ◽

A Genome ◽

Rate Deceleration ◽

A Site ◽

Hiv 1

Site-specific evolutionary rate shifts are defined as protein sites, where the rate of substitution has changed dramatically across the phylogeny. With respect to a given clade, sites may either undergo a rate acceleration or a rate deceleration, reflecting a site that was conserved and became variable, or vice-versa, respectively. Sites displaying such a dramatic evolutionary change may point to a loss or gain of function at the protein site, reflecting adaptation, or they may indicate epistatic interactions among sites. Here, we analyzed full genomes of HIV and SIV-1 and identified 271 rate-shifting sites along the HIV-1/SIV phylogeny. The majority of rate shifts occurred at long branches, often corresponding to cross-species transmission branches. We noted that in most proteins, the number of rate accelerations and decelerations was equal, and we suggest that this reflects epistatic interactions among sites. However, several accessory proteins were enriched for either accelerations or decelerations, and we suggest that this may be a signature of adaptation to new hosts. Interestingly, the non-pandemic HIV-1 group O clade exhibited a substantially higher number of rate-shift events than the pandemic group M clade. We propose that this may be a reflection of the height of the species barrier between gorillas and humans versus chimpanzees and humans. Our results provide a genome-wide view of the constraints operating on proteins of HIV-1 and SIV.

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Low Postseroconversion CD4+T-cell Level Is Associated with Faster Disease Progression and Higher Viral Evolutionary Rate in HIV-2 Infection

mBio ◽

10.1128/mbio.01245-18 ◽

2019 ◽

Vol 10 (1) ◽

Cited By ~ 3

Author(s):

Angelica A. Palm ◽

Philippe Lemey ◽

Marianne Jansson ◽

Fredrik Månsson ◽

Anders Kvist ◽

...

Keyword(s):

T Cell ◽

Disease Progression ◽

Police Officers ◽

Evolutionary Rate ◽

Virus Evolution ◽

Cell Level ◽

Immunodeficiency Virus ◽

Study Participants ◽

The Relationship ◽

Hiv 1

ABSTRACTA positive correlation between virus evolutionary rate and disease progression has been shown for human immunodeficiency virus type 1 (HIV-1) infection. Much less is known about HIV-2, the second causative agent of AIDS. We analyzed 528 HIV-2envV1-C3 sequences generated from longitudinal plasma samples that were collected from 16 study participants during a median observation time of 7.9 years (interquartile range [IQR], 5.2 to 14.0 years). Study participants were classified as faster or slower disease progressors based on longitudinal CD4+T-cell data. The HIV-2 evolutionary rate was significantly associated with CD4+T-cell levels and was almost twice as high among the faster progressors as among the slower progressors. Higher evolutionary rates were accounted for by both synonymous and nonsynonymous nucleotide substitutions. Moreover, slow disease progression was associated with stronger positive selection on HIV-2/SIVsm (simian immunodeficiency virus infecting sooty mangabey) surface-exposed conserved residues. This study demonstrated a number of previously unknown characteristics linking HIV-2 disease progression with virus evolution. Some of these findings distinguish HIV-2 from HIV-1 and may contribute to the understanding of differences in pathogenesis.IMPORTANCEThe relationship between HIV evolution and disease progression is fundamental to our understanding of HIV immune control and vaccine design. There are no clear definitions for faster and slower HIV-2 disease progression and for the relationship of the rate of progression with HIV-2 evolution. To address the hypothesis that viral evolution is correlated with disease progression in HIV-2 infection, we determined faster and slower disease progression based on follow-up data from a prospective cohort of police officers in Guinea-Bissau. The analysis showed that although the CD4+T-cell level and the decline in the level were independently associated with progression to AIDS, only the CD4+T-cell level or a combined CD4+T-cell level/decline stratification was associated with the rate of HIV-2 evolution. The HIV-2 evolutionary rate was almost twice as high among the faster progressors as among the slower progressors. Importantly, this report defines previously unknown characteristics linking HIV-2 disease progression with virus evolution.

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HIV-2 Genetic Evolution in Patients with Advanced Disease Is Faster than That in Matched HIV-1 Patients

Journal of Virology ◽

10.1128/jvi.02548-09 ◽

2010 ◽

Vol 84 (14) ◽

pp. 7412-7415 ◽

Cited By ~ 23

Author(s):

Helena Skar ◽

Pedro Borrego ◽

Timothy C. Wallstrom ◽

Mattias Mild ◽

José Maria Marcelino ◽

...

Keyword(s):

Mutation Rate ◽

Generation Time ◽

Evolutionary Rate ◽

Advanced Disease ◽

Evolutionary Rates ◽

Data Sets ◽

Genetic Evolution ◽

Synonymous Substitutions ◽

V3 Region ◽

Hiv 1

ABSTRACT The objective of this study was to estimate and compare the evolutionary rates of HIV-2 and HIV-1. Two HIV-2 data sets from patients with advanced disease were compared to matched HIV-1 data sets. The estimated mean evolutionary rate of HIV-2 was significantly higher than the estimated rate of HIV-1, both in the gp125 and in the V3 region of the env gene. In addition, the rate of synonymous substitutions in gp125 was significantly higher for HIV-2 than for HIV-1, possibly indicating a shorter generation time or higher mutation rate of HIV-2. Thus, the lower virulence of HIV-2 does not appear to translate into a lower rate of evolution.

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CXCR6-Mediated Simian Immunodeficiency Virus SIVagmSab Entry into Sabaeus African Green Monkey Lymphocytes Implicates Widespread Use of Non-CCR5 Pathways in Natural Host Infections

Journal of Virology ◽

10.1128/jvi.01626-16 ◽

2016 ◽

Vol 91 (4) ◽

Cited By ~ 13

Author(s):

Katherine S. Wetzel ◽

Yanjie Yi ◽

Sarah T. C. Elliott ◽

Dino Romero ◽

Beatrice Jacquelin ◽

...

Keyword(s):

T Cell ◽

Viral Replication ◽

Simian Immunodeficiency Virus ◽

Natural Host ◽

Immunodeficiency Virus ◽

Sooty Mangabeys ◽

Green Monkey ◽

Natural Hosts ◽

Siv Infection ◽

Hiv 1

ABSTRACT African green monkeys (AGM) and sooty mangabeys (SM) are well-studied natural hosts of simian immunodeficiency virus (SIV) that do not progress to AIDS when infected with their species-specific viruses. Natural hosts of SIV express very low levels of the canonical entry coreceptor CCR5, and recent studies have shown that CCR5 is dispensable for SIV infection of SM in vivo and that blocking of CCR5 does not prevent ex vivo infection of peripheral blood mononuclear cells (PBMC) from SM or vervet AGM. In both hosts, CXCR6 is an efficient entry pathway in vitro. Here we investigated the use of species-matched CXCR6 and other alternative coreceptors by SIVagmSab, which infects sabaeus AGM. We cloned sabaeus CD4 and 10 candidate coreceptors. Species-matched CXCR6, CCR5, and GPR15 mediated robust entry into transfected cells by pseudotypes carrying SIVagmSab92018ivTF Env, with lower-level entry through GPR1 and APJ. We cloned genetically divergent env genes from the plasma of two wild-infected sabaeus AGM and found similar patterns of coreceptor use. Titration experiments showed that CXCR6 and CCR5 were more efficient than other coreceptors when tested at limiting CD4/coreceptor levels. Finally, blocking of CXCR6 with its ligand CXCL16 significantly inhibited SIVagmSab replication in sabaeus PBMC and had a greater impact than did the CCR5 blocker maraviroc, confirming the use of CXCR6 in primary lymphocyte infection. These data suggest a new paradigm for SIV infection of natural host species, whereby a shared outcome of virus-host coevolution is the use of CXCR6 or other alternative coreceptors for entry, which may direct SIV toward CD4+ T cell subsets and anatomical sites that support viral replication without disrupting immune homeostasis and function. IMPORTANCE Natural hosts of SIV do not progress to AIDS, in stark contrast to pathogenic human immunodeficiency virus type 1 (HIV-1)-human and SIVmac-macaque infections. Identifying how natural hosts avoid immunodeficiency can elucidate key mechanisms of pathogenesis. It is known that despite high viral loads, natural hosts have a low frequency of CD4+ cells expressing the SIV coreceptor CCR5. In this study, we demonstrate the efficient use of the coreceptor CXCR6 by SIVagmSab to infect sabaeus African green monkey lymphocytes. In conjunction with studies of SIVsmm, which infects sooty mangabeys, and SIVagmVer, which infects vervet monkeys, our data suggest a unifying model whereby in natural hosts, in which the CCR5 expression level is low, the use of CXCR6 or other coreceptors to mediate infection may target SIV toward distinct cell populations that are able to support high-level viral replication without causing a loss of CD4+ T cell homeostasis and lymphoid tissue damage that lead to AIDS in HIV-1 and SIVmac infections.

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Nonpathogenic Simian Immunodeficiency Virus Infection of Sooty Mangabeys Is Not Associated with High Levels of Autologous Neutralizing Antibodies

Journal of Virology ◽

10.1128/jvi.00295-10 ◽

2010 ◽

Vol 84 (12) ◽

pp. 6248-6253 ◽

Cited By ~ 28

Author(s):

Bing Li ◽

Kelly Stefano-Cole ◽

David M. Kuhrt ◽

Shari N. Gordon ◽

James G. Else ◽

...

Keyword(s):

Simian Immunodeficiency Virus ◽

Neutralizing Antibodies ◽

Adaptive Immune Response ◽

Natural Host ◽

Subtype C ◽

Natural Host Species ◽

Immunodeficiency Virus ◽

Sooty Mangabeys ◽

High Level ◽

Hiv 1

ABSTRACT Simian immunodeficiency virus (SIV) infection of natural-host species, such as sooty mangabeys (SMs), is characterized by a high level of viral replication and a low level of generalized immune activation, despite evidence of an adaptive immune response. Here the ability of SIV-infected SMs to mount neutralizing antibodies (Nab) against autologous virus was compared to that of human immunodeficiency virus type 1 (HIV-1) subtype C-infected subjects. While high levels of Nab were observed in HIV-1 infection, samples obtained at comparable time points from SM exhibited relatively low titers of autologous Nab. Nevertheless, SM plasma with higher Nab titers also contained elevated peripheral CD4+ T-cell levels, suggesting a potential immunologic benefit for SMs. These data indicate that AIDS resistance in these primates is not due to high Nab titers and raise the possibility that low levels of Nab might be an inherent feature of natural-host SIV infections.

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