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HIV-1 and human genetic variation

Nature Reviews Genetics volume 22, pages 645–657 (2021)Cite this article

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Abstract

Over the past four decades, research on the natural history of HIV infection has described how HIV wreaks havoc on human immunity and causes AIDS. HIV host genomic research, which aims to understand how human genetic variation affects our response to HIV infection, has progressed from early candidate gene studies to recent multi-omic efforts, benefiting from spectacular advances in sequencing technology and data science. In addition to invading cells and co-opting the host machinery for replication, HIV also stably integrates into our own genome. The study of the complex interactions between the human and retroviral genomes has improved our understanding of pathogenic mechanisms and suggested novel preventive and therapeutic approaches against HIV infection.

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Fig. 1: Schematic representation of the HIV life cycle and the HLA-mediated host response.
Fig. 2: Classical and non-classical effects of HLA class I on HIV suppression.
Fig. 3: CCR5 expression modifies HIV progression.
Fig. 4: Detecting genomic signatures of host–pathogen interactions in matched host and virus samples.
Fig. 5: Antiretroviral drugs target multiple stages of the HIV life cycle.

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Authors and Affiliations

  1. National HIV and Retrovirology Laboratory at the JC Wilt Infectious Diseases Research Centre, National Microbiology Laboratory, Public Health Agency of Canada, Winnipeg, MB, Canada

    Paul J. McLaren

  2. Department of Medical Microbiology and Infectious Diseases, University of Manitoba, Winnipeg, MB, Canada

    Paul J. McLaren

  3. School of Life Sciences, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland

    Jacques Fellay

  4. Swiss Institute of Bioinformatics, Lausanne, Switzerland

    Jacques Fellay

  5. Precision Medicine Unit, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland

    Jacques Fellay

Authors
  1. Paul J. McLaren
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  2. Jacques Fellay
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The authors contributed equally to all aspects of the article.

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Correspondence to Jacques Fellay.

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Glossary

HIV/AIDS

HIV is the causative agent of AIDS, which is a state of severe immune deficiency defined as an HIV infection with either a CD4+ T cell count <200 cells/µl or the occurrence of a specific AIDS-defining illness.

CC-chemokine receptor 5

(CCR5). A β-chemokine receptor that is involved in lymphocyte trafficking. In combination with CD4, CCR5 is the major host cell receptor for HIV and interacts with gp120 in the viral envelope to promote cell entry and infection.

Cytotoxic T lymphocytes

(CTLs). Cytotoxic T cells (also called CD8+ T cells) are effector T lymphocytes that specifically kill target cells that express an appropriate peptide–MHC class I complex recognised by its T cell receptor.

Human leucocyte antigen

(HLA). A protein, encoded by one of a group of HLA genes, that presents antigens that train the adaptive immune response. HLA genes are highly variable and allelic variants encode proteins that are differentially able to present antigens based on the amino acid sequences in the peptide-binding grooves.

Epitopes

Parts of an antigen that make contact with a particular antibody or T cell receptor and are thus capable of stimulating an immune response.

Polygenic risk scores

(PRS). Statistics that are calculated by enumerating the number of risk alleles associated with a particular phenotype (often weighted by their population-level effect sizes) that are present in a single individual and comparing the individual’s score to the distribution of risk scores in the population.

Population stratification

Presence of systematic differences in allele frequencies between population subgroups owing to systematic differences in ancestry.

HIV progression

The natural disease course of HIV infection in untreated individuals, characterized by an acute phase, a chronic phase and the development of AIDS. The rate of HIV progression varies dramatically in the infected population.

HIV latency

The long-term persistence of HIV in an integrated but transcriptionally inactive form in the host genome. Because latent HIV resides in memory T cells, it persists indefinitely even in patients on suppressive antiretroviral therapy. This latent reservoir is a major barrier to curing HIV infection.

Set point viral load

(spVL). Mean log viral load (HIV RNA copies per millilitre of plasma) measured in an individual with HIV infection during the chronic phase of infection. The spVL varies substantially within a population and correlates with disease progression.

Genetic architecture

Underlying genetic basis of a given trait, in terms of variant number, effect size, allele frequency and interactions.

HIV controllers

A group of people living with HIV whose plasma HIV RNA load is spontaneously maintained at very low levels for several years (usually at least 3–5 years) in the absence of antiretroviral therapy.

Restriction factor

A host cellular protein that participates in antiviral defence by interfering with specific steps of the viral replication cycle.

Killer immunoglobulin-like receptor

(KIR). A family of highly polymorphic activating and inhibitory receptors that serve as key regulators of human natural killer cell function.

HIV target cells

The cells primarily infected by HIV, namely CD4+ T cells and macrophages, both of which are key components of a healthy immune system.

RALY-mediated degradation

A mechanism in which the RALY protein binds to the 3′ untranslated region of an mRNA to promote its degradation.

Transmitted/founder virus

The single viral variant that is responsible for a new infection after being transferred from an infected individual to an uninfected individual. Sexually transmitted HIV infections are typically established from a single transmitted/founder virus.

Genome-to-genome (G2G) studies

Methods that test the hypothesis that host genetic variability causes pathogen genetic variability and can indicate novel host restriction factors.

Treatment as prevention

Strategy to prevent the sexual transmission of HIV through the prescription of HIV medication. It is a highly effective option for preventing HIV transmission. People living with HIV who take antiretroviral drugs and maintain an undetectable viral load have effectively no risk of sexually transmitting the virus to their HIV-negative partners.

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McLaren, P.J., Fellay, J. HIV-1 and human genetic variation. Nat Rev Genet 22, 645–657 (2021). https://doi.org/10.1038/s41576-021-00378-0

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