The Science of HIV

HIV is a retrovirus — a category of virus that stores its genetic information as RNA rather than DNA, and then uses a specialised enzyme called reverse transcriptase to copy that RNA into DNA once inside a host cell. This is the reverse of the usual direction of genetic information flow (DNA → RNA → protein), which is how the family gets its name.

There are only a handful of human-infecting retroviruses, and HIV is by far the most clinically significant. The virus particle (virion) is spherical, roughly 120 nanometres across, and is wrapped in a lipid envelope studded with glycoprotein spikes — the gp120/gp41 complex — that are essential to how HIV enters cells.

HIV's primary target is the CD4+ T lymphocyte — a type of white blood cell that coordinates the adaptive immune response. The process of cell entry is highly specific and depends on molecular recognition:

1. Attachment: The gp120 spike on HIV binds to the CD4 receptor on the surface of the T cell. This interaction induces a conformational change in gp120 that exposes a second binding site.
2. Co-receptor binding: The exposed site on gp120 then binds to a co-receptor — either CCR5 (used by most sexually transmitted HIV) or CXCR4 (used by later-stage virus). This triggers the gp41 subunit.
3. Membrane fusion: gp41 undergoes a dramatic shape change, driving the viral and cell membranes together and allowing the viral contents to enter the cell.
4. Reverse transcription: Inside the cell, reverse transcriptase converts the viral RNA genome into double-stranded DNA. This step is error-prone, producing mutations that drive drug resistance and immune evasion.
5. Integration: The viral DNA, as part of a pre-integration complex, enters the nucleus. The enzyme integrase splices the viral DNA into the host chromosome — permanently. This integrated form is called the provirus.
6. Replication: The host cell's own machinery transcribes the provirus into new viral RNA and mRNA, which is translated into viral proteins. New virions assemble at the cell membrane and bud off, maturing with the help of HIV protease.

CD4+ T cells are orchestrators of the immune response — they activate cytotoxic T cells, stimulate antibody production by B cells, and coordinate defences against a wide range of pathogens. HIV destroys them through several mechanisms:

• Direct lysis: the budding of large numbers of new virions physically ruptures the cell membrane.
• Immune-mediated killing: infected cells displaying viral proteins on their surface are recognised and killed by cytotoxic T lymphocytes.
• Pyroptosis: a form of inflammatory cell death triggered by HIV that is particularly destructive during acute infection.
• Bystander killing: HIV proteins circulating in the bloodstream can trigger apoptosis (programmed cell death) in uninfected CD4+ cells.

A healthy immune system maintains around 500–1500 CD4 cells per cubic millimetre of blood. As HIV progressively destroys these cells, the immune system loses its ability to fight off infections and cancers that a healthy system would suppress. Below 200 cells/mm³, the risk of AIDS-defining illnesses rises sharply.

The most fundamental obstacle to curing HIV is the latent reservoir. When HIV infects long-lived resting CD4+ memory T cells, it can integrate its DNA and then simply go dormant — entering a state of latency where the provirus is not actively transcribed and no viral proteins are produced.

In this latent state, the infected cell is invisible to the immune system and to antiretroviral drugs, which only act on actively replicating virus. These dormant cells can persist for decades — potentially the lifetime of the individual. When the immune system is eventually suppressed or ART is stopped, latent virus can reactivate.

The latent reservoir is established within days of initial infection — before most people would think to seek treatment. Even patients who started ART very early (within hours of exposure) still harbour latent reservoirs. This is the central biological reason why stopping antiretroviral therapy (outside of closely monitored clinical trials) reliably leads to viral rebound.

Modern antiretroviral therapy (ART) works by targeting different enzymes or steps in the HIV replication cycle simultaneously. Using multiple drugs at once prevents the virus from developing resistance, since the probability of mutating around two or three drugs simultaneously is astronomically low. Current drug classes include:

• Nucleoside/Nucleotide Reverse Transcriptase Inhibitors (NRTIs): Mimic the building blocks of DNA. When incorporated by reverse transcriptase, they terminate DNA chain elongation, stopping viral DNA synthesis.
• Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs): Bind directly to the reverse transcriptase enzyme and change its shape, blocking its function without acting as a chain terminator.
• Integrase Strand Transfer Inhibitors (INSTIs): Block the integrase enzyme from splicing viral DNA into the host chromosome. Now the preferred backbone of first-line therapy due to their potency and tolerability.
• Protease Inhibitors (PIs): Block HIV protease, the enzyme that cleaves viral protein precursors into functional proteins during virion maturation. Infected cells produce viral particles that are non-infectious.
• Entry Inhibitors / CCR5 Antagonists: Block either the gp120–CD4 interaction or the CCR5 co-receptor binding step, preventing viral entry into cells entirely.

PEP (Post-Exposure Prophylaxis) works by administering antiretroviral drugs before HIV can establish a permanent reservoir. After sexual exposure, HIV must travel through mucosal tissue, infect dendritic cells or CD4+ T cells locally, and then disseminate to lymph nodes — a process that takes several days. PEP interrupts this early replication phase. If started within 72 hours and completed consistently over 28 days, it can prevent the virus from establishing the integrated proviral reservoir. After 72 hours, local replication has progressed too far for the drugs to reliably interrupt establishment.

PrEP (Pre-Exposure Prophylaxis) typically involves the combination tenofovir/emtricitabine (Truvada or generic equivalent). These drugs accumulate as active metabolites in rectal and genital mucosal cells. When HIV enters this tissue, the drugs are already present in concentrations sufficient to block reverse transcriptase before integration can occur. Crucially, the concentration in rectal tissue is much higher than in cervicovaginal tissue, which is why PrEP efficacy is exceptionally high for receptive anal intercourse and somewhat more dependent on strict adherence for vaginal exposure.

The U=U principle is one of the most important findings in HIV science. When ART suppresses HIV to undetectable levels (typically defined as below 200 copies/mL of blood, though most people on ART achieve below 50), sexual transmission does not occur. This has been confirmed across three large prospective studies (HPTN 052, PARTNER, and PARTNER 2) involving thousands of sex acts without a condom between serodiscordant couples.

Biologically, this makes sense: HIV is transmitted through infectious viral particles in genital secretions. When ART suppresses replication to undetectable levels in blood, it similarly suppresses viral load in seminal and vaginal fluids. Without viral particles, there is nothing to transmit. The latent reservoir still exists — dormant proviruses are present — but latent virus is not released and does not appear in genital secretions in sufficient quantities to cause infection.

Several strategies are being investigated to eliminate the latent reservoir:

• "Shock and kill": Latency-reversing agents (LRAs) are used to reactivate the dormant provirus, forcing infected cells to produce viral proteins that flag them for immune destruction — while ART suppresses any newly produced virus. Results in humans have been disappointing so far; LRAs have successfully reactivated latent virus but have not significantly reduced reservoir size.
• "Block and lock": The opposite strategy — using compounds to drive the latent reservoir into a deeper, permanent state of silencing so it can never reactivate. This would represent a "functional cure" even if the reservoir persists.
• Gene editing (CRISPR-Cas9): Researchers have demonstrated that CRISPR can excise integrated HIV DNA from infected cells in animal models. Translating this to a safe and scalable human therapy remains a major challenge due to off-target cutting risks and the need to reach every cell in a distributed reservoir.
• Stem cell transplantation: A small number of patients have achieved apparent viral remission after bone marrow transplants from donors with a rare mutation (CCR5-delta32 homozygous) that confers natural resistance to most HIV strains. This is not scalable as a therapy but provides proof of concept that the virus can be eliminated.