Hiv And Aids

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HIV structure

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Enveloped
Diploid genome, contains 2 +ssRNAs
Two envelope glycoproteins - GP120 and GP41 - required for attachment and entry (major target for Ab neutralization)
Carries reverse transcriptase
Easily inactivated

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HIV genome complexity

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Produce reverse transcriptase/integrase/protease proteins
Envelope glycoproteins GP120 and GP41
Encode regulatory proteins
LTR (long terminal repeats) controls gene expression

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HIV attachment and entry

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Attaches via GP 120 to CD4
Chemokine receptors are co-receptors required for infection of macrophages and T cells
Presence/absence of receptor/co-receptor is primary determinant of tropism
GP41 fuses envelope to plasma membrane
Transported to nucleus

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HIV replication

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In nucleus
Reverse transcriptase makes dsDNA (provirus)
Provirus integrated, passed vertically
Host RNA pol II transcribes, makes viral RNA when host cell activated
- LTR activated
Viral RNAs made, translated, packaged

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HIV release

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Immature viruses released from host cell by budding
After release, viral protease cleaves viral gag protein, produces mature particle

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Antigenic drift in HIV

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Reverse transcriptase makes lots of errors
Extensive antigenic drift in GP120
Massive antigenic variation, rapid generation of drug-resistant mutants

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HIV infection of CD4+ cells

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HIV viral swarm binds to DCs, which travel to lymph nodes
Passes from DC to target cell
Binds to CD4/chemokine receptors on T cell/macrophage

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HIV tropism

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CD4+ lymphocytes and macrophages
Macrophage-tropic strains - present at early times of infection, called R5 viruses, require CD4 and CCR5 to enter host
T cell-tropic strains - appear later in infection, require CD4 and CXCR4 to enter host, bad prognosis

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HIV replication in T cells and macrophages

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In T lymphocytes, results in cell death/dysfunction, immunosuppression, and AIDS
In monocytes/macrophages - does not always result in cell death, can cause AIDS dementia, inflammatory disease in other organs

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HIV normal progressors

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Absence of treatment, typical course spans 10 years
Undergoes replication in first 3 months, establishes viremia, decline in CD4+ T cells
Clinical latency - little virus detectible, no symptoms, but large amount of replication in lymph nodes
Clinical course parallels CD4 count; when falls below 200/microliter = AIDS

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Other HIV presentations

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Rapid progressors
Long-term non-progressors - most heterozygous for CCR5 gene defects
HIV-resistant individuals - remain uninfected despite long-term HIV exposure - most homozygous for CCR5 mutations

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HIV epidemiology

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HIV-1 primarily outside of Africa, HIV-2 in central Africa
Central and southern Africa have highest number of infections
Spread blood-to-blood, sexual, or perinatal
Amount of virus in fluid affects risk - Blood>>semen>>vaginal>>saliva

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HIV risk factors

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MSM still at highest risk
IV drug abuse
Heterosexual contact - esp. male to female
In US - African-Americans and urban poor are disproportionately affected

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HIV time to develop AIDS

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Ranges from 2 to >10 years
Average 7 years

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Acute retroviral syndrome

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2 weeks to several months after initial infection
Flu-like symptoms or mild mononucleosis-like symptoms
Transient drop in CD4 cells
MC symptoms - fever, lymphadenopathy, rash (palms and soles included), pharyngitis, myalgia, arthralgia

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HIV constitutional symptoms

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After clinical latency of 1-10 years
Include fatigue, malaise, lymphadenopathy, chronic diarrhea, severe weight loss
Blood shows decreased CD4+ T cell count, reversal of CD4/8 ratio

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Progressive generalized lymphadenopathy

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PGL
Defined as lymph node enlargement to at least 1 cm at 2 or more extra-inguinal sites for more than 3 months
Classic constitutional symptom of HIV disease

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Slim disease

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HIV patients often with drastic weight loss
Esp HIV-2 infection

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Opportunistic protozoa in AIDS

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Toxoplasma

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Opportunistic fungi in AIDS

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Candida albicans
Pneumocystis jiroveci

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Opportunistic bacteria in AIDS

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Mycobacterium avium-intracellulare
Mycobacterium tuberculosis

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Opportunistic viruses in AIDS

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CMV - esp CMV retinitis
VZV - multi-dermatomal Zoster
JC virus - PML
EBV - hairy leukoplakia
HCV

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Opportunistic cancers in AIDS

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Kaposi's sarcoma (rare outside of HIV)

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MC infectious cause of death in HIV patients

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HCV cirrhosis

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HIV neurologic disease

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AIDS dementia complex late in AIDS
Poor memory, apathy, behavior changes, loss of motor control

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Pediatric AIDS

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Symptoms within 2 years, death within another 2
Wasting, generalized lymphadenopathy, diarrhea, failure to thrive, recurrent opportunistic infection, neurologic disorders

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Clinical HIV diagnosis

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Severe wasting and chronic diarrhea (sudden weight loss)
Simultaneous fungal, bacterial, or parasitic infections and/or unusual cancers

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Nonspecific HIV lab tests

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Depressed CD4 count (<200/microliter is AIDS)
Inverted CD4/8 ratio

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Direct detection of HIV DNA/RNA

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Using RT-PCR - most sensitive test, test of choice for determining HIV viral load
Used to diagnose congenital/pediatric HIV infection
- Presence of antiviral IgM cannot be used - HIV suppresses IgM response in infants

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HIV serology

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Lab tests of choice for screening blood, diagnosing infection in adults
Anti-HIV ELISA
RIBA/Western blot assay
Rapid screening tests

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Anti-HIV ELISA

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Screening test
Test for anti-HIV capsid IgG by EIA
Takes 6 months for immune response to develop
Must do 2-3 tests at least six months apart

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RIBA/Western blot assay

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If positive obtained by EIA, RIBA confirms results (some false + with EIA)

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Nucleoside analogue reverse transcriptase inhibitors

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NRTIs
Includes Zidovudine (AZT), Lamvudine (3TC)
Are viral reverse transcriptase inhibitors, cause DNA chain termination

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Non-nucleoside analogue reverse transcriptase inhibitors

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NNRTIs
Non-nucleoside drugs that inhibit HIV reverse transcriptase
Systemic treatment of HIV-1 and 2

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Protease inhibitors

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Inhibit HIV protease
Prevent production of mature virions
For systemic treatment of HIV-1 and 2

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Fusion inhibitors

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Includes Enfuvirtide and T20
Inhibitor of HIV/host cell fusion
Systemic treatment of HIV-1

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CCR5 antagonists

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Includes Maraviroc
Inhibitor of HIV envelope/host cell fusion that is specific for CCR-5 tropic HIV

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Proviral integration inhibitors

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INSTIs
Includes Raltegravir
Inhibits HIV integrase enzyme

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HAART

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Highly aggressive anti-retroviral therapy
Combination therapy with 2 NRTIs plus 1 protease inhibitor, NNRTI, or integrase inhibitor
Treatment of choice
Effective at reducing viral load, delaying/preventing AIDS onset
Lowers transmission risk
Multiple drug resistant HIV is a growing problem

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Perinatal HIV prophylaxis

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All pregnant women should be screened for HIV infection early during pregnancy
HAART prophylaxis has nearly eliminated perinatal transmission in US

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Post-exposure prophylaxis in adults

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HAART

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Pre-exposure prophylaxis (PrEP)

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Tenofovir + Emtricitabine (FTP) preexposure chemoprophylaxis

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Confirmation of effective HIV treatment

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Essential to closely monitor treatment - develops resistance quickly
Test:
Viral load (RT-PCR)
Drug resistance profile
CD4 count at patient's initial visit, then every 3-4 months

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Anti-viral drug resistance testing

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Perform before initiating therapy and if treatment fails

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Salvage therapy

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If HAART fails due to drug resistance
Failure indicated by increased viral load, decreased CD4 count, or development of frank symptoms