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  • Review Article
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The immune response during acute HIV-1 infection: clues for vaccine development

Nature Reviews Immunology volume 10, pages 11–23 (2010)Cite this article

Key Points

  • The early virological factors in HIV-1 infection, including transmission and the nature of the founder virus, can affect the time course of viraemia through the early peak to set point.

  • The identification of patients within the first few weeks of HIV-1 infection has provided early evidence of immune system damage, including massive apoptosis of CD4+ T cells, which is associated with the presence of apoptotic microparticles and TRAIL (tumour necrosis factor-related apoptosis-inducing ligand) in the blood, and damage to germinal centres in mucosal lymphoid tissues.

  • The first innate immune responses include the appearance of acute-phase proteins, early cytokine storm and activation of natural killer (NK) cells. An innate immune response to HIV-1 can be damaging, however, as it can draw susceptible T cells to the infection foci.

  • The first T cell response controls the founder virus by killing infected T cells. However, the T cell response also selects mutational changes in the founder virus, allowing immune evasion.

  • The first B cell response consists of early immune complexes, followed by non-neutralizing antibodies against the founder virus and then the slow development of broadly acting neutralizing antibodies. Development of vaccines that rapidly induce broadly acting neutralizing antibodies might be beneficial in preventing HIV infection.

  • Understanding the early events and immune responses is crucial to devising vaccine strategies that can improve the weak protection offered by current HIV vaccines that are being trialled, such as the RV144 (Thai) efficacy trial.

Abstract

The early immune response to HIV-1 infection is likely to be an important factor in determining the clinical course of disease. Recent data indicate that the HIV-1 quasispecies that arise following a mucosal infection are usually derived from a single transmitted virus. Moreover, the finding that the first effective immune responses drive the selection of virus escape mutations provides insight into the earliest immune responses against the transmitted virus and their contributions to the control of acute viraemia. Strong innate and adaptive immune responses occur subsequently but they are too late to eliminate the infection. In this Review, we discuss recent studies on the kinetics and quality of early immune responses to HIV-1 and their implications for developing a successful preventive HIV-1 vaccine.

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Figure 1: Definition of acute HIV-1 infection.
Figure 2: Early events in acute HIV-1 infection.
Figure 3: The cytokine storm in acute HIV-1 infection.
Figure 4: Early T cell selection of virus escape mutations in acute HIV-1 infection.
Figure 5: Composite alignment of the earliest innate and adaptive immune responses detected after HIV-1 transmission.

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Acknowledgements

This work was supported by the Center for HIV/AIDS Vaccine Immunology (CHAVI) grant A1067854-03. Additional support came from the Medical Research Human Immunology Unit, the National Institute for Health Research, Oxford Biomedical Research Centre and grants 38643 and 37874 from the Bill and Melinda Gates Foundation. A.J.M. and P.B. are Jenner Investigators and P.B. is supported by a Jenner Fellowship. G.D.T is supported by the US National Institutes of Health, grants RO1AI052779, U19AI067854, AI068618 and AI64518 and the Bill and Melinda Gates Foundation (grant 38619). We are grateful to members of the CHAVI Scientific Leadership Group, N. Letvin, M. Cohen, J. Sodroski, D. Goldstein and G. Shaw for scientific input and for reviewing this manuscript, and to the CHAVI Clinical Core Investigators and their patients for participation in the CHAVI studies cited in this review.

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Authors and Affiliations

  1. Medical Research Council Human Immunology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, OX3 9DS, UK

    Andrew J. McMichael & Nilu Goonetilleke

  2. The Jenner Institute, University of Oxford, Oxford, OX3 7DQ, UK

    Persephone Borrow

  3. Duke Human Vaccine Institute, Duke University School of Medicine, Durham, 27710, North Carolina, USA

    Georgia D. Tomaras & Barton F. Haynes

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  1. Andrew J. McMichael
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Correspondence to Andrew J. McMichael.

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Glossary

Viral set point

The time at which plasma viraemia settles to a stable level (within approximately 3–6 months from the onset of HIV infection). Viral set point is partially predictive of both how quickly HIV infection will progress and the risk of HIV transmission.

Founder virus

A transmitted virus or a virus that gives rise to all virus quasispecies in an infected individual.

Viral fitness

The ability of a virus to replicate in a given environment. By definition in in vitro studies, a drug-resistant virus has greater ability to replicate than wild-type virus when measured in the presence of a drug, similarly a T cell escape mutant will replicate better than wild-type virus when co-cultured with specific T cells. The T cell-resistant or drug-resistant virus may replicate less well than the wild type when the selective force is withdrawn.

Langerhans cell

A type of dendritic cell that is resident in the epithelial layer of the skin and mucosa.

Single-genome amplification

A method of DNA sequencing that uses high-fidelity polymerase and minimizes PCR amplification, thereby excluding sequence errors and recombination events that may be introduced during amplification.

Clade

HIV is subdivided, based on degree of sequence divergence, into three major groups, M, N and O; group M is subdivided into 10 subtypes or clades, of which clade C is the predominant subtype worldwide (prevalent in subSaharan Africa and India) and clade B is the most studied subtype (prevalent in North America and Eastern Europe).

Quasispecies

A distribution of non-identical but closely related viral genomes. The entire distribution forms an organized cooperative structure, which acts like (quasi) a single unit (species).

APOBEC cytidine deaminases

A family of host antiviral proteins that introduce multiple mutations, including stop codons, in retroviruses by deaminating cytosine residues in nascent retroviral cDNA.

Germinal centre

A highly specialized and dynamic microenvironment located in peripheral lymphoid tissues (for example, the spleen or lymph nodes). It is the main site of B cell maturation, leading to the generation of memory B cells and plasma cells that produce high-affinity antibody.

Regulatory T (TReg) cell

A type of CD4+ T cell that is characterized by its expression of forkhead box P3 (FOXP3) and high levels of CD25. TReg cells can suppress many types of immune responses.

Genome-wide association study

An approach that involves rapidly scanning single nucleotide polymorphism markers across the complete genomes of many individuals to find genetic variations associated with a particular disease.

Single nucleotide polymorphisms

(SNPs). Single nucleotide variations in genomic DNA sequences in which one of the four nucleotides is substituted for another. SNPs are the most frequent type of polymorphism in the genome and can be used to map genes connected by linkage disequilibrium.

Bw4 motif

The amino acid sequences at positions 77–83 in the α1 domain of HLA class I heavy chains. There are four Bw4 motif sequences, which differ only at positions 77 (Asn, Asp or Ser) and 80 (Ile or Thr). The Bw4 motif is involved in the recognition of certain HLA alleles by killer immunoglobulin-like receptors.

Seroconversion

Development of a detectable concentration of pathogen-specific antibodies in the serum as a result of infection or immunization. Seroconversion normally occurs in patients with HIV-1 infection 3–4 weeks following infection, around Fiebig stage III, typically when plasma virus loads are reaching their peak.

Acute-phase proteins

A group of proteins, including C-reactive protein, serum amyloid A, complement components and fibrinogen, that are secreted into the blood in increased or decreased quantities by hepatocytes in response to trauma, inflammation or disease. These proteins can be inhibitors or mediators of inflammatory processes.

T helper 17 cells

A subset of CD4+ T helper cells that produce interleukin-17 (IL-17) and that are thought to be important in antibacterial and antifungal immunity and may also have a role in autoimmune diseases. Their generation involves IL-23 and IL-21, as well as the transcription factors RORγt (retinoic acid-related orphan receptor-γt) and STAT3 (signal transducer and activator of transcription 3).

Envelope proteins

Envelope proteins of HIV are initially produced as a precursor glycoprotein of 160 kDa (gp160) that is cleaved to generate gp120 and gp41. Three gp120 molecules and three gp41 molecules are thought to combine in a trimer to form the envelope spike.

Fiebig stages

Stages of HIV-1 infection. They are defined by a series of laboratory tests that measure the emergence of HIV-1-specific antibodies, viral RNA and viral antigens.

Class switching

The somatic-recombination process by which the class of immunoglobulin is switched from IgM to IgG, IgA or IgE.

Peyer's patches

Specialized lymphoid follicles localized in the submucosa of the small intestine and appendix.

Antibody-dependent cell-mediated cytotoxicity

(ADCC). A cytotoxic mechanism by which an antibody-coated target cell is directly killed by a leukocyte that expresses FcRs, such as an NK cell, macrophage or neutrophil.

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McMichael, A., Borrow, P., Tomaras, G. et al. The immune response during acute HIV-1 infection: clues for vaccine development. Nat Rev Immunol 10, 11–23 (2010). https://doi.org/10.1038/nri2674

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