HIV Replication and Pathogenesis

Question 1

What are the most common methods of transmission of HIV? What were the three viruses introduced three separate times into humans?

Answer 1

1. Unprotected sex with an infected partner
2. Sharing needles with infected person (usually illicit drug use, not necessarily blood transfusion);
   O, M, N forms of SIV

Question 2

What is not linked to HIV transmission? What has been eliminated pretty much as risk factors for HIV transmission?

Answer 2

1. Casual contact
2. Exposure to saliva or urine
3. Blood-sucking insects;
   transmission from infected mother to fetus (treat with antiviral drugs), infection from blood products (screening)

Question 3

Who is at greatest risk of acquiring AIDS in US? Which races are at most risk of acquiring HIV? Which gender is more likely to be infected?

Answer 3

Gay/bisexual men; AA’s and Hispanics more so than whites; women more so than men

Question 4

Outline HIV exposure and subsequent infection

Answer 4

1. Few virions breach vaginal or rectal epi and establish infection by first targeting lymphocytes that express CD4 and a co-receptor (like lymphocytes or macrophages); however R0 is small since it’s difficult for virus to find target cell
2. After infecting macrophages and dendritic cells, the infected cells produce virions and migrate to lymph node –> further infection
3. Virions go from regional lymph nodes to GALT, and then spleen, brain, liver, lung

Question 5

Main symptoms of acute HIV infection

Answer 5

Systemic: Fever, weight loss
Central: malaise, headache
Lymph nodes: lymphadenopathy
Mouth: sores, thrush
Esophagus: sores
Muscles: Myalgia
Liver and Spleen: enlargement
Gastric: nausea and vomiting

Question 6

HIV is a(n) _____ virus; it is otherwise categroized as what? How many copies per virion? What does this virus resemble structurally?

Answer 6

RNA; retrovirus, lentivirus, ssRNA, + strandl two copies;

RNA…5’cap, genes, then poly-A tail

Question 7

Early on in infection, what does HIV bind? Later on, what will it bind and what is induced? How has the virus changed in this time?

Answer 7

CD4 receptor and CCR5 receptor (e.g. CD4 T helper cells and macrophages, respectively); will bind CXCR4 and CD4 receptor which can induce SYNCTIUM (due to MUTATIONS IN ENV CHANGE FOR CXCR4 BINDING)

Question 8

What does the HIV env consist of? What is binding the CCR and CD4 receptors? What allows for insertion in the target cell membrane?

Answer 8

TM (gp41) and SU (gp120); the SU moiety; the fusion peptide on TM

Question 9

What are the five steps leading up to phase 1 conclusion of HIV replication?

Answer 9

1. Attachment and membrane fusion
2. Uncoating and partial capsid disintegration
3. RT of SSRNA genomes to DNA (uses dNTPs in the cytoplasm)
4. Migration of circular genomes to the nucleus (bound to HIV protein integrase which has nuclear localization signal directing to the uterus)
5. HIV provirus integrates into host chromosome (permanent event and creates reservoir of latent virus throughout body; need to try and eradicate latency)
   INTEGRATION marks end of phase 1

Question 10

What marks the start of phase 2 of HIV replication?

Answer 10

RNA Pol II recruited and several types of mRNA transcribed, spliced, exported to cytoplasm

Question 11

With mRNA made in the nucleus, what now can be made to continue with phase 2? (Transcription and translation)

Answer 11

1. mRNA translation on cytoplasm ribosomes and ribosomal frameshifting creates more Gag»_space;Gag-Pol;
2. genomic mRNAs are full-length transcripts;
3. some short mRNAs encode Env and this Env mRNA translated at rough ER into protein cleaved into SU and TM
4. Env matures in Golgi
5. Secretory vesicles traffic Env to plasma membrane
6. Other proteins and genomic mRNA accumulate at plasma membrane, concentrating in lipid rafts

Question 12

To round out phase 2, what is formed upon viral exit? ____ _______ cleaves _____ into subunits that result in capsid assuming what conformation?

Answer 12

Virions due to budding from plasma membrane (NOT INFECTIOUS);
HIV protease; Gag; trapezoidal shape

Question 13

What is HIV protease most important for?

Answer 13

Cleave Gag to form infectious particles

Question 14

What mediates attachment and entry of HIV into T cells and macrophages? What can Env help induce among T cells?

Answer 14

Env; can fuse infected T cells with uninfected T cells (syncytium that are lethal for T cells and more virulent than non-syncytium-inducing strains)

Question 15

Stages of HIV disease

Answer 15

1. Exposure to virus (transmission)
2. Primary HIV infection (acute phase)
3. Seroconversion
4. Clinical latent period
5. Early symptomatic HIV infection
6. AIDS (CD4 count below 200/mm3)
7. Advanced HIV infection (CD4 below 55/mm3)

Question 16

In course of HIV infection and progression to AIDS, how does this occur? What controls the virus for decades perhaps (ie latency)?

Answer 16

1. CD4+ and CCR5+ cells infected by HIV
2. Env mutations enable HIV infection of CD4+ and CXCR4+ cells
3. Step 2 means that CD8+ T cells are waning, risk of AIDS increasing
4. Viral load will climb and CD4+ T cells drop as AIDS progresses;
   NK cells and CTL’s

Question 17

Over the course of the disease, how many virions can be produced? How many T cells turn over?

Answer 17

Billions of virions; one billion T cells turn over during persistent infection