Mednotes

L20 I&I Immunology of HIV

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tagsinfectionandimmunity, lecture
aliasesL20 I&I Immunology of HIV

14 min read

Overview

This lecture covers HIV virology and replication, how HIV is transmitted and establishes infection across mucosal surfaces, the natural history of untreated infection (acute infection, clinical latency, progression to AIDS), why the anti-HIV immune response (especially CD8+ T cells) ultimately fails to control the virus, and how progressive CD4+ T cell depletion produces the opportunistic infections and cancers that define AIDS.

Epidemiology and origin

  • HIV is an emerging pathogen: first known HIV-1 infection Kinshasa, DRC, 1959; first AIDS cases recognised in the United States 1981; HIV-1 identified in France and the US 1983; HIV-2 isolated from West Africa 1986; high rates of HIV-1 infection first reported in East Africa 1986; HIV-1 seroprevalence >40% in parts of southern Africa by 2003.
  • HIV originated as a zoonotic infection: phylogenetic analysis shows HIV-1 (groups M, N, O) and HIV-2 (groups 2A, 2B) each arose from separate cross-species transmission events of simian immunodeficiency virus (SIV) from chimpanzees (SIVcpz) and sooty mangabeys/other monkey species, i.e. multiple independent introductions of SIV into humans.
  • 2024 global figures: 40.8 million people living with HIV; 1.3 million new infections; 0.63 million AIDS deaths. An estimated 0.7% (range 0.6-0.8%) of adults aged 15-49 worldwide are living with HIV, with prevalence highest in southern Africa.

Virology and replication cycle

  • HIV is a retrovirus of the lentivirus genus: lipid envelope, two copies of single-stranded RNA genome (~9.2 kbp), with long terminal repeats (LTR) flanking the genome (LTR-gag-pol-vif-vpr/vpu-env(tat/rev/nef)-LTR).
  • Key proteins:
    • Envelope glycoproteins (env): gp120 and gp41
    • Nucleocapsid (gag): p24
    • Essential enzymes (pol): integrase, protease, reverse transcriptase
    • Accessory proteins: Tat, Rev, Nef, Vif, Vpr, Vpu
  • Replication cycle (numbered steps):
    1. Attachment: Env (gp120) binds CD4
    2. Fusion
    3. Uncoating
    4. Reverse transcription (RNA genome to cDNA, via reverse transcriptase)
    5. Nuclear import, forming a pre-integration complex (PIC)
    6. Integration of HIV cDNA into the host genome (integrase; involves LEDGF) - the integrated genome is now called the provirus
    7. Transcription (by host RNA polymerase II) from the 5’ LTR promoter to 3’ LTR
    8. Nuclear export of full-length and spliced transcripts (via CRM1)
    9. Translation: accessory viral proteins (Vif, Vpu, Rev, Tat) and Gag/Gag-Pol polyproteins
    10. Assembly
    11. Budding
    12. Release
    13. Maturation (protease activated with budding, cleaves Gag and Gag-Pol into their component proteins), producing an infectious new virion
  • Entry sequence in detail: gp120 binds CD4 with high affinity (CD4 is expressed on CD4+ T cells and on some macrophages and dendritic cells) -> conformational change allows gp120 to bind a co-receptor (CCR5, found on memory CD4+ T cells, macrophages and DCs; or CXCR4, found on T cells, particularly naive T cells later in infection) -> this exposes gp41, which mediates membrane fusion and entry of the nucleocapsid.
  • Transcription detail: occurs only from integrated provirus and only in activated cells; there is no transcription in resting cells, which is the basis of latency. Host transcription factors NFkB and NFAT (both involved in T cell activation) bind promoters in the viral LTR to drive transcription by RNA polymerase II.
  • Translation/assembly/maturation detail: Gag and Pol are translated as polyproteins; Env is translated as gp160 and cleaved by host protease. After assembly, budding and release, viral protease (activated with budding) cleaves Gag and Gag-Pol into their respective mature proteins (maturation), producing an infectious virion.

Transmission

  • Four transmission routes: sexual transmission, injection drug use, exposure to blood/blood products via transfusion, and vertical (mother to fetus/infant) transmission.
  • Sexual transmission is the most common route. Infectious virus is present in semen and at mucosal surfaces. Per-contact transmission probability varies by:
    • Type of sex: receptive anal 1.4%, insertive anal 0.11%, receptive vaginal 0.08%, insertive vaginal 0.04%, oral (receptive or insertive) low.
    • Viral load: transmission risk is higher during acute infection and late-stage infection (both high viral load states).
    • Presence of STIs, which enhance transmission via inflammation (more target cells) and disruption of the mucosal barrier (ulcers, making entry easier).
  • Transmission across mucosal barriers: HIV crosses the mucosal lumen and infects sub-mucosal CD4+ T cells, macrophages and dendritic cells, producing local amplification. gp120 binds C-type lectins on dendritic cells, and infected CD4+ T cells and dendritic cells then transport HIV to lymphoid tissue, where it reaches follicular dendritic cells and B cells in the germinal centre.

Natural history of untreated infection

  • Primary/acute infection (roughly weeks 0-9): acute HIV syndrome with wide dissemination of virus and seeding of lymphoid organs. Plasma HIV RNA spikes sharply; CD4+ T cell count falls sharply, then partially recovers as the immune response (especially CD8+ T cells) begins to control viral replication (weeks 6-12).
  • Early events specifically include massive depletion of CD4+ memory T cells from the intestine (with large numbers of activated CD4+ T cells present), widespread dissemination of HIV to lymphoid tissues, and depletion of CD4+ T cells from blood. Endoscopic and histological comparison of HIV-negative vs HIV-positive gut mucosa shows loss of lymphoid aggregates and marked loss of CD4+ T cells in HIV-positive tissue.
  • Clinical latency (roughly year 1 to year 8): viral RNA sits at a relatively stable “viral setpoint”; CD4 count declines steadily over years while the person is largely without symptoms early on, developing constitutional symptoms later in this phase.
  • AIDS (roughly years 8-11): CD4 count declines steeply and viral load rises again, leading to opportunistic disease and death (around years 10-11).
  • Over the course of infection: antibodies against HIV Env rise and plateau; HIV-specific CTL responses rise then gradually decline; antibodies against HIV p24 rise then decline; infectious virus in plasma spikes early, drops, oscillates at a low level through the long middle (latent) phase, then rises again near the end.

Why the CD8+ T cell response fails to control HIV

  • CD8+ T cells normally kill virus-infected cells: naive T cells are stimulated by antigen-presenting cells (APC) presenting antigen via MHC class I to the T cell receptor plus co-stimulation (CD80/CD86-CD28); IL-2/IL-2 receptor signalling drives proliferation and differentiation into effector T cells; active effector T cells then recognise and kill virus-infected target cells.
  • T cell receptors recognise peptide epitopes bound to MHC: epitopes are usually buried within protein structure and must first be broken down into peptide fragments; the epitope peptide binds a self MHC molecule; the TCR binds the MHC-peptide complex, with the CD4 or CD8 co-receptor also engaging the MHC molecule. CD4+ T cells recognise MHC class II; CD8+ T cells recognise MHC class I.
  • Reasons HIV-specific CD8+ T cells fail to control infection:
    1. High rate of mutation leading to immune escape: HIV mutates within CD8+ T cell epitopes so that mutant virus is no longer recognised by the patient’s existing CD8+ T cells (illustrated by a single patient’s Tat epitope, where an escape mutation progressively became fixed in the viral population over about three years - this specific dataset is an illustrative example, not core content to memorise). Underlying drivers of high mutation and diversity: reverse transcriptase and host RNA polymerase II both lack proofreading ability (~0.25 mutations per cycle of replication); high viral turnover generates roughly 10^10 virions per day; together these produce huge intra-individual viral diversity. Within a host, infection typically starts from a single “founder” virus, which then diversifies rapidly under immune selection pressure (mutations accumulate in CD8+ T cell epitopes), in contrast to the much broader diversity seen across the whole HIV population.
    2. Loss of CD4+ T cell help impairs CD8+ T cell responses: CD4+ T cell help supports CD8+ T cell proliferation, effector differentiation and memory formation via co-stimulation through the APC (CD80/86, 4-1BBL) and IL-2. As HIV depletes CD4+ T cells, this help pathway is lost, impairing CD8+ T cell responses.
    3. Loss of CD4+ T cell help also impairs B cell responses (helper CD4+ T cells normally engage B cells via CD40/CD40L and cytokines IL-4/IL-5/IL-6 to drive B cell proliferation and differentiation into memory and antibody-secreting plasma cells); loss of CD4+ T cells disrupts this pathway too.
    4. Neutralising antibodies are limited: few broadly neutralising epitopes exist on the HIV envelope, due to sequence variation, conformational masking, and a host-derived, poorly immunogenic glycan shield covering the envelope spike. About 20% of patients do develop broadly neutralising antibodies, but this does not alter disease progression.
    5. Latently infected cellular reservoirs: latently infected CD4+ T cells carry integrated but transcriptionally silent provirus, express no antigen and are therefore invisible to the immune system; these latently infected memory CD4+ T cells have a long half-life, and HIV replicates again when the infected T cell is activated. Macrophages and dendritic cells can also be infected by HIV without being killed, serving as additional reservoirs.
  • Taken together, HIV persists despite an active immune response because of (1) high mutation rate driving immune escape, (2) loss of CD4+ T cell help for both CD8+ T cells and B cells, and (3) a latently infected cellular reservoir.

AIDS: CD4 depletion and its clinical consequences

  • Depletion of CD4+ T cells leads to Acquired Immunodeficiency Syndrome (AIDS) because CD4+ T cells provide help to multiple arms of the immune response:
    • Loss of CD4+ T cell help for CD8+ T cells increases susceptibility to intracellular infections (e.g. cytomegalovirus, CMV) and protozoan infections (e.g. toxoplasmosis), as well as increased risk of cancers such as Kaposi’s sarcoma (caused by HHV8).
    • Loss of CD4+ T cell help for B cells increases susceptibility to mucosal infections, e.g. pneumonia.
    • Loss of TH1 (CD4+) help for macrophages: TH1 cells normally activate macrophages via CD40 ligand-CD40 interaction and IFN-gamma signalling, enhancing macrophage killing of intracellular bacteria; loss of this help increases susceptibility to intracellular bacterial infections such as Mycobacterium tuberculosis.
  • Specific opportunistic conditions correlate with CD4 count (values approximate, “details not important until clinical years” per the lecturer, but included here for completeness):
    • 300-400 cells/mm3: pulmonary Mycobacterium tuberculosis; oral/pharyngeal candidiasis
    • 200-300 cells/mm3: pulmonary non-tuberculous mycobacterial infection; recurrent pneumonia
    • 100-200 cells/mm3: disseminated Mycobacterium tuberculosis; oesophageal candidiasis; Pneumocystis jiroveci pneumonia; Kaposi’s sarcoma
    • <100 cells/mm3: disseminated Mycobacterium avium complex; toxoplasmosis; CMV retinitis; primary brain lymphoma

The "People living with HIV 2024" statistics box in the source deck appears positioned beneath the origin/zoonosis slide's title but is treated here as data belonging with the epidemiology figures, per the transcript's note.

Self-test

  1. Describe the steps of the HIV replication cycle from attachment through to release of a mature virion.
  2. Describe the sequence of receptor/co-receptor binding events that allows HIV to enter a target cell, naming the receptors involved.
  3. Explain why HIV transcription occurs only in activated, integrated cells and not in resting cells, naming the host transcription factors involved.
  4. List the four main routes of HIV transmission.
  5. List the factors that influence the probability of HIV transmission per sexual contact.
  6. Describe how HIV crosses a mucosal barrier and reaches lymphoid tissue.
  7. Describe the pattern of CD4+ T cell count and plasma HIV RNA over the course of untreated infection, from primary infection through clinical latency to AIDS.
  8. Distinguish MHC class I from MHC class II in terms of which T cell subset recognises each.
  9. Explain the three main reasons why HIV-specific CD8+ T cell responses fail to control HIV infection long-term.
  10. Explain why few broadly neutralising antibody epitopes exist on the HIV envelope.
  11. Describe what makes latently infected CD4+ T cells invisible to the immune system, and what triggers renewed HIV replication in them.
  12. A patient with a CD4 count of 150 cells/mm3 presents with oesophageal candidiasis. Explain, in terms of CD4+ T cell help, why loss of CD4+ T cells increases susceptibility to this and to intracellular bacterial infections such as tuberculosis.
  13. Integrative: explain how high mutation rate, loss of CD4+ T cell help, and the latent reservoir together allow HIV to persist despite an ongoing CD8+ T cell response, and how this persistence ultimately leads to AIDS.

Answers

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