HIV/AIDS

Question 0

Viral replication of HIV

Answer 0

“specific interaction between envelope glycoprotein gp120 and a CD4 receptor protein”
“The life cycle steps consist of attachment, co-receptor binding, fusion, reverse transcription, integration, transcription (by host cell RNA polymerase), translation, cleavage of precursor proteins, nucleocapsid assembly, budding, virion maturation.”
“Binding facilitated by co-receptor of CCR5 superfamily.”

Question 1

Structure of HIV

Answer 1

“enveloped. The nucleocapsid is of uncertain symmetry and contains two identical strands of plus-stranded RNA (single stranded RNA, + sense). The virion carries three HIV enzymes: reverse transcriptase, integrase, and protease.”

Question 2

Other factoids about HIV

Answer 2

“HIV proteins and HIV RNA are assembled into a proteinaceous viral capsid near the cell plasma membrane. (The host cell has an innate enzyme called APOBEC3G that disrupts HIV RNA, however the viral Vif protein disables this innate resistance function of APOBEC3G).”
“The virion at this point is not yet fully mature and HIV protease also functions within the virion, after the virion has budded, to mature the infectivity of HIV virions.”
“host cell RNA polymerase that make the viral mRNA (and the viral genome) have no proofreading functions. Thus these replication enzymes are error-prone and often make random mutations in HIV. It is estimated that there is one mutant virus made for every 5 or 10 HIV virions that mature.”

Question 3

Transmission of HIV

Answer 3

“primarily by sexual contact or via transfer of infected blood.”
IV Drug Use
“Mother-to-child transmission (during pregnancy, during delivery, or by breastfeeding), blood transfusions, needle stick injury, occupational exposure risk.”
“Higher HIV levels in blood (viral load), mucosal injury, and the presence of infections (STD) at the mucosal site significantly increases the risk of transmission”
“Injection drug use is probably a higher risk than sexual routes. Anal sex is a higher risk that vaginal sex, and the receptive partner is at the higher risk in both cases”

Question 4

Prevention of HIV

Answer 4

No vaccine.
Condoms, circumcisions in some population, microbicidals, rapid testing, not sharing needles and discarding donated bloods

Question 5

Clinical symptoms of acute HIV infection

Answer 5

“This acute HIV infection often results in a mononucleosis-like syndrome with fever, enlarged lymph nodes, headache, fatigue, and sometimes the appearance of a rash.”

Question 6

Diagnosis of acute HIV infection

Answer 6

“viral load (HIV RNA in blood) is extremely high, but the infected person has not yet seroconverted (anti-HIV antibodies will develop later typically within a few months).”

“There is a dramatic decline in the number of circulating CD4+ T lymphocytes during acute HIV infection. ”

Question 7

Aftermath of acute HIV infection

Answer 7

Robust immune activation following acute HIV infection: activation-induced CD4+ depletion also occurs. CTLs trying to neutralize infected CD4+ cells and cytokines are mounted. Viral load returns to a set point, HIV viral set point. This correlates with seroconversion (2 months after)

Question 8

Clinical symptoms of chronic HIV infection

Answer 8

“It is important to recognize that most individuals with chronic HIV infection are asymptomatic, thus epidemiology (risks) and screening are necessary to make the diagnosis.”
“The HIV virus evades immunological pressure by mutating to variant HIV that are capable of escaping immune surveillance”
Chronic activation of immune system leads to decreased ability to control HIV, activation induced cell death.

Question 9

Diagnosis of chronic HIV infection

Answer 9

“A slow and relentless decline in the CD4+ T cell count occurs during chronic HIV infection.”

“Chronic HIV infection is diagnosed with HIV serology (ELISA followed by confirmatory Western blot to HIV antigen).”

Question 10

Diagnosis of AIDS

Answer 10

Prognosis is made after determining the viral load set point. Women, although starting with lower set point, progress to AIDS at a faster rate. Also look at CD4+ count.
Definition of AIDS: CD4+ cell count <15%

Question 11

Clinical symptoms of AIDS

Answer 11

“After the HIV+ individual reaches the clinical definition of AIDS, death typically occurs within 2 years. Death is primarily due to infections (opportunistic), cancers (“Cervical, anal, and brain cancers appear more frequently in AIDS”)”
Kaposi’s sarcoma, Burkitt’s lymphoma
Increased risk of Hep B/C infection, herpes simplex/cytomegalovirus/EBV reactivation
Psychiatric and cardiovascular complications

Question 12

Treatment of AIDS

Answer 12

“HAART”, highly active antiretroviral therapy.”
Compared to monodrug therapy, “more potent in reducing viral load and also reduces the chances of selecting HIV mutants that are resistant”
Could be followed by immune reconstitution therapy, where rapid expansion f CD4+ exacerbates inflammation of concurrent opportunistic infection

Question 13

Six drug classes of antiretroviral therapy

Answer 13

1. Nucleoside Reverse Transcriptase Inhibitor (terminate growing HIV cDNA)
2. Non-nucleoside Reverse Transcriptase Inhibitor: “Mechanism of action is to inhibit reverse transcriptase enzyme activity in an allosteric manner and block synthesis of HIV DNA.”
3. Protease Inhibitor
4. CCR5 antagonist
5. Fusion inhibitors (interferes with gp41 fusion complex)
6. Integrase inhibitor

1, 2, 3 are used in HAART, 4, 5, 6 when drug resistance occurs