Lecture 7: HIV (Part 2) PubHlth 80

Five stages of untreated HIV time course

1) Window period, 2) acute infection, 3) clinical latency, 4) early stage disease, 5) AIDS.

Window period

Time after infection when testing can give a false negative, because not enough virus or antibodies have built up.

Acute infection

First months after infection: very high viral load, non-specific symptoms. The body makes antibodies against HIV, but they don't stop the infection.

Clinical latency (stage)

The virus keeps replicating and killing CD4 cells, but bone marrow regenerates enough, so there are no clinical symptoms. May last over 10 years or under 1 year.

Major HIV transmission routes

1) Sex (the major route worldwide), 2) mother to child (pregnancy, delivery, breastfeeding; major in developing countries), 3) broken skin (injected drug users, needle pricks, blood transfusions).

What influences HIV transmission during unprotected sex?

The type of sex and the viral load of the HIV-positive partner. Chance per encounter is relatively low but accumulates.

Can you tell someone's HIV status by looking?

No. Specific tests are needed.

Three types of HIV test

1) Antibody test (antibodies against HIV proteins), 2) antigen test (HIV proteins), 3) NAT (HIV genomes).

Screening vs validation in HIV testing

Antibody and antigen tests are quick and easy but less sensitive than NAT, so are used for screening. A positive result is validated with NAT.

NAT (Nucleic Acid Test)

Detects the HIV genome in blood using PCR. Very quantitative: gives viral load (HIV genomes per ml).

PCR (Polymerase Chain Reaction)

Amplifies specific DNA segments exponentially (1, 2, 4, 8 copies…), so it detects tiny amounts. 30 cycles gives about a billion copies (2^30).

HIV antibody test

Detects antibodies to HIV proteins, showing exposure. Antibodies take time to appear (primary immune response), so testing too soon can give a false negative (window period).

ELISA

Enzyme-linked immunosorbent assay, the most common antibody test. Steps: viral protein (e.g. gp120) fixed to a dish, incubated with the person's serum, HIV-specific antibodies stay bound after washing, a stain detects retained human antibodies (color = positive). Current ELISAs are better than 99.9% accurate.

Why is HIV testing key to control?

People don't develop symptoms for years but are infectious. UN estimates 86% of people with HIV know their status (14% don't).

HIV as a manageable chronic condition

With effective antivirals HIV replication can be inhibited, T cell levels maintained or restored, and people can stay healthy (like diabetes or arthritis), though life expectancy is still lower. Without ART most infected people develop disease.

U=U

Undetectable = Untransmittable. People with HIV who maintain an undetectable viral load (virally suppressed) on ART cannot sexually transmit the virus.

Primary infection

Many people lack symptoms at first. High levels of infectious virus in blood. HIV levels then drop and antibodies develop ('HIV positive'), but they don't control the infection.

How HIV escapes the immune system

1) Antibodies can't stop infection. 2) Very high mutation rate in the envelope protein (the main target of neutralizing antibodies) lets it escape antibodies. 3) Latent virus expresses no proteins so isn't detected as non-self. 4) Cell-to-cell spread avoids neutralizing antibodies. This makes a vaccine harder.

Initial disease

Untreated, most progress to AIDS. Symptoms usually begin when CD4 counts drop below 400 cells per ml of blood. Moderate immune failure, mainly in skin and mucosal tissues.

Opportunistic infection

An infection that usually can't infect or cause disease in people with a functional immune system. A hallmark of immune dysfunction. Also seen in organ transplant recipients on immunosuppressants, inherited immunodeficiencies (SCID, 'bubble kids') and lymphomas.

Common opportunistic infections in initial disease

Candida overgrowth in the mouth (fungus), shingles (reactivation of the chickenpox virus) and tuberculosis (bacteria).

Candida

A fungus related to baker's yeast, normally on skin and mucosa without disease. ~50% of AIDS patients have overgrowth. Oral candidiasis (thrush) forms furry white plaques. Vaginal overgrowth is a 'yeast infection', common in HIV-infected women.

AIDS (systemic immunodeficiency)

CD4 counts drop below 200 cells per ml of blood. Severe immune dysfunction. HIV levels are no longer controlled and rise exponentially. Opportunistic infections and some virus-induced cancers are common.

AIDS progression and cause of death

Without ART, symptoms in most people begin ~10-12 years after infection. Breakdown is gradual. Death results from infection or cancer, not directly from HIV. Many infections are latent ones (herpesviruses, toxoplasma) that the failing immune system can no longer control.

Examples of AIDS-related infections

Pneumocystis pneumonia (PCP, fungal), systemic fungal infections, parasites, reactivation of latent viruses (hepatitis B and C, cytomegalovirus, herpes simplex, JC virus). All rare in people with a functional immune system.

AIDS-related cancers

Virus-associated cancers: Kaposi's sarcoma (tumor of blood vessels, KSHV), non-Hodgkin lymphoma (EBV), cervical cancer (papillomavirus). T cells normally sense 'altered self' and kill cancer cells. No higher frequency of non-viral cancers (patients probably die first).

T-helper cell turnover in AIDS

AIDS patients lose ~1 billion T-helper cells a day, and bone marrow makes almost as many. The deficiency is from very low CD4 numbers. If virus replication is blocked (ART), CD4 cells can build back up.

AZT

Azido-thymidine, first FDA-approved HIV drug (1987). Blocks HIV reverse transcriptase. Not new: made in 1964 as a cancer drug and found active against a mouse retrovirus in 1974.

Limitations of AZT

Side effects at high doses (anemia, liver toxicity, heart toxicity), and only a limited treatment window (about 1.5 extra years of life expectancy) before the virus mutated and became resistant.

Protease inhibitors and combination therapy

Approved 1995. Block the viral protease that cleaves the polyprotein. Alone no better than RT inhibitors (similar activity, quick resistance), but they allowed the first combination therapies.

Why does combination therapy work?

Resistance to each drug is rare (e.g. 1/500), so resistance to two is 1/250,000 and to three about 1/125,000,000.

Current HIV drug landscape

8 classes of antivirals targeting RT (2 classes), protease, integrase, viral entry (3 classes) and capsid (new, 2022). Combos of 2-4 drugs are available in one pill taken once daily. Biktarvy (2 RT inhibitors + 1 integrase inhibitor) is the most common.

Viral suppression

Current ART gives no detectable HIV in the blood, even though virus persists in latent reservoirs. Patients have routine CD4 and viral load checks. Signs of treatment failure lead to viral genome sequencing and a new drug combination.

Future HIV drugs

Efforts focus on reducing pill frequency: long-acting once-a-week, every 3 months or every 6 months options.

PEP (post-exposure prophylaxis)

ART given for a defined period to HIV-negative people after an exposure ('morning after pill'). Common scenarios: healthcare worker needle stick, rape victims. Must be started within 72 hours.

PrEP (pre-exposure prophylaxis)

Daily ART for HIV-negative people likely to be exposed (e.g. partners of HIV-positive people or high-risk groups) to minimize chance of infection.

PrEP drugs

Truvada (daily pill, 2 RT inhibitors), Descovy (daily pill, basically same, both Gilead), Apretude (injection every two months, an integrase inhibitor; spelled 'Apertude' on the slide). Users must be HIV-negative at the start and tested every 3 months.

Why are PrEP users tested every 3 months?

Slide asks 'why?'. Reasoning: to confirm they remain HIV negative, since a person who becomes infected while taking PrEP would be on incomplete therapy that could drive drug resistance.

Lenacapavir

Newly developed (2022) first-in-class capsid inhibitor that binds the HIV capsid and disrupts the life cycle. PURPOSE 1 and PURPOSE 2 phase 3 trials succeeded as single-agent PrEP injected every 6 months. FDA approved June 18, 2025.

Elimination of HIV

Theoretically possible by vaccination and long-acting PrEP since HIV is limited to humans (like smallpox, and polio nearly). But no candidate vaccine has shown efficacy: the main hurdle is HIV's diversity and rapid mutation (a moving target). Trials continue (incl. a Moderna mRNA vaccine).

HIV cure: the major hurdle

The latent reservoir of infected memory T-cells. ART doesn't affect it, and cells can reactivate and spread HIV again even if all currently infected cells are killed.

Elite controllers

HIV-positive people with very low viremia and high CD4 counts (about 1 in 300). Mechanisms include host genetics such as CCR5 deletion.

CCR5

A co-receptor for HIV, needed for viral entry. Non-functional in ~1% of Caucasians due to a gene mutation. CCR5-negative individuals are highly resistant to HIV.

Berlin patient (Timothy Brown)

Had HIV and an AIDS-related lymphoma. Received a bone marrow transplant from a CCR5-negative donor; remaining HIV couldn't infect the new cells and he stayed undetectable without ART. At least four others cured similarly.

Issues with CCR5 transplant cures

CCR5 mutation is rare and bone marrow transplant is risky. Theoretically genetic engineering could delete CCR5 before transplant.

Kick and kill

Strategy to remove the latent reservoir (~1 million latent infected T cells). Reactivate latent HIV with drugs ('kick'), so cells become susceptible to ART. Activated cells release HIV and die, and ART handles new infections.