Lecture 6: HIV (Part 1) PubHlth 80

Virus vs bacteria: structure

Virus: non-cellular. Bacteria: cellular.

Virus vs bacteria: size

Virus: usually below 200 nm. Bacteria: over 1,000 nm.

Virus vs bacteria: genetic material

Virus: variable (DNA or RNA). Bacteria: DNA.

Virus vs bacteria: replication

Virus: needs a host. Bacteria: independent.

Virus vs bacteria: antibiotics and antivirals

Antibiotics: no effect on viruses, yes (broad spectrum) on bacteria. Antivirals: yes for viruses (specific for each virus), no for bacteria.

Defining feature 1: obligate intracellular parasite

Viruses cannot replicate or make more of themselves outside the cells they infect.

Defining feature 2: two parts of the life cycle

The extracellular virion and the 'virocell' (an infected cell taken over by a virus).

Defining feature 3: genetic material

Can be RNA or DNA, which affects the life cycle and the viral proteins needed for replication.

Defining feature 4: capsid

Keeps the viral genetic material safe while outside a host cell.

Defining feature 5: naked vs enveloped

Naked viruses have no envelope. Enveloped viruses have a capsid wrapped in a lipid bilayer taken from the host cell membrane during budding.

How does a virus infect a host?

It must contact a susceptible cell. Skin protects (outer layers are dead cells that can't be infected). Inside surfaces (mucosa) have their own defenses. Understanding entry routes is key to control.

Six ways pathogens gain entry

Inhalation, ingestion, broken skin, sex, mother to child, eyes.

Six stages of a typical virus infection

1) Binding to receptor, 2) entry into cell, 3) expression of viral genes, 4) replication of viral genome, 5) assembly of new progeny, 6) egress out of cell.

Lytic virus

The infected cell is killed ('lysed') at the end of infection.

Non-lytic (persistent / carrier) virus

The cell survives and continually produces virus particles.

Latency (viral)

Virus genetic material is hidden in the cell and no virus is made. It can be reactivated, leading to production of infectious virus.

Why are established viral infections hard to treat?

Viruses rely on the host cell for most processes, so it is hard to block the virus without killing host cells. Antibiotics work because bacteria/fungi have different biochemical machinery.

Antivirals

Drugs that specifically inhibit a viral process. Typically effective against only a specific virus. A number have been developed for HIV.

Basic treatment for most viral infections

Manage symptoms.

Best approach to viral infection

Prevention: public health and sanitation, and vaccines to induce immunity.

Lifelong vs short-term immunity from vaccines

Lifelong: smallpox, measles. Short-term: influenza and SARS-CoV-2. There is no HIV vaccine (yet).

HIV

Human Immunodeficiency Virus. A retrovirus and the causative agent of AIDS. Two types: HIV-1 and HIV-2. Origin: Old World primates.

Hallmarks of retroviruses

Reverse flow of genetic information from RNA to DNA, and integration of the DNA into the host genome. They are enveloped viruses.

Retrovirus structure

RNA genome packaged in a protein capsid, inside a lipid bilayer envelope. The capsid contains the genome plus RT (reverse transcriptase) and IN (integrase), two viral enzymes not present in human cells, so they are drug targets.

gp120

HIV envelope protein that binds the CD4 receptor on T-cells.

Stages of the HIV infection cycle

1) Binding to CD4 and co-receptors, 2) entry (fusion), reverse transcription, integration into host DNA, then either latency (no transcription or replication until reactivation) or transcription and protein translation, replication, assembly and egress.

CD4

Surface protein that is the cell receptor for HIV. Present on CD4 T-cells and some other cells.

HIV target cells

CD4 T-cells. They produce virus and are usually killed by it, except memory T-cells, in which the virus remains latent. CD4 depletion occurs over years, leading to AIDS.

Reverse transcription

Converting RNA to DNA, done by reverse transcriptase. Goes against the central dogma (DNA to RNA to protein). 'Retro' = Latin for 'backwards'.

Why must RT be in the HIV virion?

Cells don't have an RT enzyme (the virus can't steal one), and cells can't make mRNA from RNA, so the virus can't make proteins until its RNA is converted to DNA.

Why does HIV evolve rapidly?

RT is a 'messy' enzyme that makes many mistakes during reverse transcription, causing many mutations, so the virus evolves quickly to escape our immune system, drugs and vaccines.

Integration / integrase (IN)

Integrase, present in the capsid like RT, inserts the viral DNA into the host genome. Occurs after reverse transcription.

Latency and reactivation in retroviruses

Retroviruses can keep their genome quiet for decades. Since the genome is integrated, every cell division copies it. No transcription during latency. In HIV, latency is established in long-lived memory T-cells. Activation of the memory T-cell activates transcription, producing new HIV particles.

Why are latently infected cells unaffected by antiviral therapy?

Slide asks 'why??'. Reasoning: no viral transcription or replication is happening, so drugs aimed at those steps have nothing to act on.

HIV assembly, egress and maturation

Assembly occurs on the host plasma membrane where the viral polyprotein meets the viral RNA genome and the immature virion buds off. The immature virion is non-infectious. The viral protease cleaves the polyprotein, making mature, infectious virus.

Why is the HIV protease a major drug target?

Maturation by protease cleavage is crucial for viral infectivity.

Polyprotein

Humans: one gene to one transcript to one protein. Some viruses: one gene to one transcript to a large polyprotein cleaved into many viral proteins.

HIV milestones

AIDS first recognized 1981. Virus discovered 1983. First anti-HIV drug (AZT) FDA-approved 1987. First potent drug combination 1995.

HIV origin

Entered humans from primates that carry SIV (simian immunodeficiency virus). HIV-1 from chimpanzees, HIV-2 from sooty mangabeys. Spread to African hunters in about the early 1920s. First US cases traced to the 1960s. Different HIV-1 types and HIV-2 are several independent cross-species events.

Why is HIV so genetically diverse?

1) Frequent mutation in reverse transcription (about 1 error per replication cycle). 2) Extensive replication (millions of new virions and infected cells each day). 3) Multiple cross-species jumps. This makes vaccine development hard.

HIV variability compared with other viruses

HIV genetic variation in a single infected person can exceed the SARS-CoV-2 diversity in the entire world. HIV-1 variants (clades) have distinct geographical distributions.

From HIV to AIDS

HIV infects and depletes CD4+ T cells (T-helper cells), causing immunodeficiency. AIDS is the late-stage disease, when the immune system is too damaged to fight off diseases and certain cancers.

AIDS time course (untreated)

Initial infection (often flu-like), then about 8-10 years of asymptomatic period (clinical latency), then AIDS with opportunistic infections and cancer.

Clinical latency vs viral latency

Viral latency: a quiet infected cell (memory T-cell), no viral proteins, invisible to immune system, unaffected by antivirals, can reactivate. Clinical latency: a period of good health with continuous viral replication, while CD4 levels stay high because bone marrow replaces killed cells. Antivirals are very effective then.

HIV pandemic status

~44 million people have died from AIDS-related illness. ~1.2 million live with HIV in the US (38,793 new infections in 2024).

New HIV infections per day (2025)

About 3,400: ~50% in sub-Saharan Africa, ~250 in children under 15, ~3,100 in adults (1,400 adult women, 1,000 young people aged 15-24, 540 young women 15-24).

AZT and early HIV antivirals

AZT, the first RT inhibitor, approved 1987. Resistance emerged quickly due to high mutation rates. Current treatments combine drugs against multiple targets.

ART (antiretroviral therapy)

Combination HIV drugs targeting RT, integrase, protease, capsid assembly, receptor binding and fusion. Highly effective at preventing AIDS but does not get rid of HIV.