HIV

• 1. Introduction

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  Without treatment, the average survival time after infection with HIV runs between 9 and 11 years, depending on the subtype. That number describes a slow collapse. HIV does not strike quickly. It settles into the very cells the body uses to defend itself, then waits. The virus can remain dormant in a human body for up to ten years after primary infection, causing no symptoms at all. During that silence, it integrates itself into a person's own DNA, hiding from the immune system it is steadily dismantling. How does a microbe this small, roughly one hundred thousand times smaller in volume than a single red blood cell, learn to outwit the human immune system? Why does it carry two copies of its own genome instead of one? And how did a virus of chimpanzees and monkeys cross into people, then spread across continents? These are the questions that follow.

• 2. The Cells It Hunts

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  Helper T cells, the CD4+ T cells, sit at the center of the immune system, and HIV targets them directly. It also infects macrophages and dendritic cells. Once inside, the virus drives CD4+ T cell numbers down through several routes at once. Some cells die by pyroptosis after abortive infection. Uninfected bystander cells die by apoptosis. The virus kills infected cells directly, and CD8+ cytotoxic lymphocytes destroy infected cells they recognize. When CD4+ T cell numbers fall below a critical level, cell-mediated immunity is lost. The body then becomes progressively more open to opportunistic infections and cancers, which marks the development of AIDS. There is a cruel logic to which cells fall first. To actively produce virus, a cell needs transcription factors present, the most important being NF-kappa B, which is upregulated when T cells become activated. The cells most likely to be entered and killed by HIV are precisely those actively fighting infection.

• 3. Anatomy Of A Virion

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  Roughly spherical and about 120 nanometres across, the HIV particle packs an extraordinary amount into a tiny shell. Inside sit two copies of positive-sense single-stranded RNA, coding for the virus' nine genes, wrapped in an ovoidal capsid built from around 2,000 copies of the protein p24. The RNA binds tightly to nucleocapsid proteins and to the enzymes the virus will need later, including reverse transcriptase, proteases, ribonuclease, and integrase. A matrix of the protein p17 surrounds the capsid and holds the particle together. The outer envelope is stolen property. When a new virus buds from a host cell, it takes a lipid bilayer from that cell's membrane, studded with host proteins and relatively few copies of HIV's own envelope protein. That envelope protein forms a spike: a cap of three gp120 molecules on a stem of three gp41 molecules anchored in the envelope. Encoded by the env gene, the spike lets the virus attach to target cells and fuse with their membranes. Because it is the sole viral protein on the surface, the spike is a major target for vaccine work, and it is also one of the most densely glycosylated molecules known. Over half the mass of the spike is N-linked glycans. They are packed so tightly that they shield the protein beneath from antibodies, and so densely that they stall as immature high-mannose glycans not normally found on human cell surfaces. Almost every broadly neutralising antibody identified so far comes from patients infected for months to years, and each binds to or is adapted to cope with those glycans. The unusual sugar coat is both a shield and, eventually, a clue.

• 4. The Replication Cycle

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  Reverse transcriptase makes the first move. Shortly after the capsid enters the cell, this enzyme frees the single-stranded RNA genome and copies it into complementary DNA. The process is extremely error-prone, and the mutations it produces can drive drug resistance or help the virus evade the immune system. The enzyme also degrades the viral RNA as it builds DNA, then makes a sense strand from the antisense copy, producing double-stranded viral DNA. Integrase then splices that DNA into the host cell's own genome, where it can lie dormant in the latent stage of infection. The gp160 spike begins entry by binding CD4 on the target cell with high affinity. Once gp120 latches onto CD4, the envelope complex changes shape, exposing its binding domains for a chemokine co-receptor, usually CCR5 or CXCR4. That second attachment lets the fusion peptide of gp41 pierce the cell membrane. Repeat sequences in gp41 then collapse the protein into a hairpin shape, pulling the two membranes together so they fuse. Assembly closes the loop. The Env polyprotein gp160 travels through the endoplasmic reticulum to the Golgi apparatus, where the enzyme furin cleaves it into gp41 and gp120. The Gag and Gag-Pol polyproteins gather at the inner plasma membrane with the viral RNA, and the particle buds out. That budded virion is still immature. Only after the packaged viral protease cuts the Gag polyproteins into matrix, capsid, and nucleocapsid proteins does the particle mature, and only mature virions can infect another cell. That protease step is exactly where antiretroviral drugs of the protease inhibitor class strike.

• 5. A Machine Built To Mutate

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  About ten billion virions can be generated every day in an infected person, and that speed feeds an unmatched capacity for change. The mutation rate runs around 3 times 10 to the minus 5 per nucleotide base per replication cycle, and some estimates push it as high as 4.1 times 10 to the minus 3 substitutions per base pair. That makes HIV the microbe with the highest known mutation rate by far. Recombination adds another layer. Each HIV-1 particle carries two RNA genomes, and during reverse transcription the nascent DNA can switch back and forth between them, a process called copy-choice. Anywhere from two to twenty recombination events per genome can happen in a single replication cycle, rapidly reshuffling genetic information. A 2014 study estimated that about 15 to 20 percent of all HIV mutations come from recombination. Why carry two genomes at all? Bonhoeffer and colleagues proposed that template switching by reverse transcriptase acts as a repair process for breaks in the single-stranded RNA. Hu and Temin argued that recombination is an adaptation for repairing damage in the RNA genomes. HIV-1 infection causes chronic inflammation and reactive oxygen species, which may break the single-stranded RNA, so Michod and colleagues suggested recombination repairs that genome damage with new variation as a byproduct. On that view, two damaged RNA copies can yield one undamaged DNA genome, and the benefit returns at every replication cycle.

• 6. Tropism And Resistance

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  Viral tropism describes which cell types a virus will infect, and for HIV-1 the answer turns on co-receptors. Macrophage-tropic strains, now called R5 viruses, use the beta-chemokine receptor CCR5 and can replicate in both macrophages and CD4+ T cells. Almost every primary HIV-1 isolate uses CCR5, regardless of genetic subtype. Macrophages appear to be among the first cells infected, and in the tonsils and adenoids of infected patients they fuse into multinucleated giant cells that pour out huge amounts of virus. T-tropic strains, now called X4 viruses, use the alpha-chemokine receptor CXCR4 instead. In patients infected with subtype B, a co-receptor switch often appears in late-stage disease, as variants that infect T cells through CXCR4 emerge. These X4 variants replicate more aggressively, causing rapid T cell depletion, immune collapse, and the opportunistic infections that mark the arrival of AIDS. Between 40 and 50 percent of AIDS patients in subtype B studies can harbour viruses of this syncytia-inducing phenotype. Some people are simply harder to infect. People with the CCR5-delta32 mutation are resistant to the R5 virus, because the mutation leaves HIV unable to bind that co-receptor. The same receptor logic shapes risk in other ways. Reactivation of herpes simplex virus-2 in people with genital herpes raises the number of CCR5-enriched CD4+ T cells in ulcerated genital skin, persisting even after the ulcer heals, and this contributes to a two- to threefold increased risk of acquiring HIV.

• 7. Two Viruses, Two Origins

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  HIV-1 and HIV-2 are two distinct species, and they came from different animals. HIV-1 is more virulent and more infective, and causes the majority of infections globally. HIV-2 transmits poorly and is largely confined to West Africa. In 2020 the International Committee on Taxonomy of Viruses approved new names for both: Lentivirus humimdef1 for HIV-1 and Lentivirus humimdef2 for HIV-2. Both are believed to have crossed from non-human primates in West-central Africa in the early 20th century. HIV-1 appears to have originated in southern Cameroon through the evolution of SIVcpz, a simian immunodeficiency virus of wild chimpanzees, specifically the subspecies Pan troglodytes troglodytes. HIV-2's closest relative is SIVsmm, a virus of the sooty mangabey, an Old World monkey of littoral West Africa from southern Senegal to western Cote d'Ivoire. A telling change happened in the jump. In most SIVs, the nef gene suppresses T cell activation, downregulating inflammatory cytokines and signals affecting T cell trafficking. In HIV-1 and in SIVcpz, nef has lost this function and no longer inhibits T-cell activation. Without it, T cell depletion becomes more likely, which leads toward immunodeficiency. Genetic studies place the most recent common ancestor of the HIV-1 M group at around 1910, an estimate linked to colonialism and the growth of large African cities. In eastern Leopoldville, now Kinshasa, as many as 45 percent of female residents were thought to be involved in sex work as of 1928, and around 15 percent of all the city's residents were infected with a form of syphilis as of 1933. Genital ulcers raise transmission manyfold. The earliest well-documented human case dates to 1959 in the Belgian Congo, and a sixteen-year-old male named Robert Rayford in the United States presented with symptoms in 1966 and died in 1969.

• 8. Naming An Epidemic

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  On the 18th of May 1981, the first news story on an exotic new disease appeared in the gay newspaper New York Native. That year, AIDS was first clinically observed in the United States, in a cluster of injection drug users and gay men with no known cause of impaired immunity, showing symptoms of Pneumocystis pneumonia, a rare opportunistic infection. Researchers at the NYU School of Medicine then studied gay men developing Kaposi's sarcoma, a previously rare skin cancer. As cases multiplied, a CDC task force formed to track the outbreak. The disease struggled to find a name. The CDC sometimes called it by the diseases linked to it, such as lymphadenopathy. The general press coined GRID, for gay-related immune deficiency. The CDC, looking at the affected communities, coined the 4H disease, singling out homosexuals, heroin users, hemophiliacs, and Haitians. After it became clear the disease was not isolated to the gay community, AIDS was introduced at a meeting in July 1982, and by September 1982 the CDC began using that name. The credit for finding the virus itself became contested. In 1983, two research groups, one led by the American Robert Gallo and one by the French investigators Francoise Barre-Sinoussi and Luc Montagnier, independently reported a novel retrovirus in AIDS patients, publishing in the same issue of the journal Science. Gallo's group called their virus HTLV-III. Montagnier's group, working from a patient with swollen neck lymph nodes and physical weakness, named theirs lymphadenopathy-associated virus, or LAV, and showed its core proteins differed immunologically from HTLV-I. Gallo admitted in 1987 that the virus he claimed to have discovered in 1984 was in reality one sent to him from France the year before. As the two viruses turned out to be the same, LAV and HTLV-III were renamed HIV in 1986. A third discovery is less often told. Jay A. Levy at the University of California, San Francisco, independently found the AIDS virus in 1983 and named it the AIDS associated retrovirus, ARV. His strains were very different from the others, and showed for the first time the heterogeneity of HIV isolates, with several remaining classic examples of the AIDS virus found in the United States.