HIV Flashcards

Question

CCR5 inhibitor

Answer 1

- **Maraviroc** - Binds CCR5 and alters its conformation - Inhibits HIV binding to CCR5 - **NOTE: this antiretroviral binds to a host protein** - Mechanisms of resistance: \*HIV develops affinity for CXCR4 chemokine receptors \*pre-existing variants that use CXCR4 will be selected for \*HIV develops affinity for the drug-bound CCR5 conformation

Answer 2

- Raltegravir (Isentress and MK-0518) - MOA: \*integrase binds to the ends of the DNA provirus and helps to form the "preintegration complex" (PIC) \*it cleaves two nucleotides from each 3' end of the provirus and then binds to host cell's DNA \*it catalyzes a covalent joining (strand transfer) of the viral DNA 3' ends to the cell's DNA- inhibited by **raltegavir** **\***the gaps are filled, presumably w/a host enzyme

Answer 3

- Antiretroviral drugs disrupt productive infection, not latent - While antirretroviral therapy inhibits active viral replication, it provides selective pressure for drug resistance - Latency/sporadic reactivation from viral reservoirs makes it unlikely that HIV will be completely cleared from an infected individual \*multidrug resistance will not develop during latency

Answer 4

- Productive infection in activated CD4 T cells \*loss of CD4 T cells via direct HIV-induced cell lysis or apoptosis or CD8- mediated cell killing (1/2 life about 0.5 days) - Nonproductive infection of resting CD4 T cells \*pre-integration latency- short term HIV reservoir \*impaired reverse transcription results in accumulation of incomplete viral cDNA transcripts \*cDNA transcripts trigger an inflammatory form of cell suicide (pyroptosis) - Post-integration latency \*proviral DNA integrates into host chromosomes \*T cells differentiate into memory cells-**long term HIV reservoir**

Answer 5

- Short term reservoirs \*pre-integration latency in resting CD4 T cells \*extracellular virus particles trapped on follicular dendritic cells \*productive, persistent infection of monocyte-macrophage lineage cells \*latent infection of monocyte-macrophage lineage cells - Long term reservoir \*post-integration latency in memory CD4+ T cells

Answer 6

- **R5 viruses** \*binds **CCR-5** chemokine receptors \*responsible for majority of viral transmission \*nonsyncytia-inducing strains (NSI) \*macrophage tropic- previous designation - R5 viruses persist throughout the infection - Quasispecies appear after viremia peaks \*closely related viral genomes; have some variability \*result of point mutations within the viral genome

Answer 7

- **X4 viruses** \*binds **CXCR-4** chemokine receptors \*occurs in about 50% of patients \*syncytia-inducing strains (SI); **more cytopathic** \*involves acquiring point mutations in the env gene - Some viruses use both co-receptors (R5X4) \*occurs in later stage patients

Answer 8

- Immune response limits the productive infection, but doesn't eliminate it \*productive infection still occurs (lymph nodes) \*steady state viral load until T cells are depleted; viral set pint - Persistent, low level productive infection \*macrophages; dendritic cells etc. - Latent infection \*memory T cell \*possibly monocyte lineage cells including hematopoietic stem cells \*can reactivate =\> productive infection - Dont have AIDS at clinical latency; you are HIV+; you dont have AIDS until your immune system has been compromised to the point where you are developing opportunistic infections (\<200 CD4 T cells in a mircoliter) NOTE: clinical latency in an HIV+ individual is not the same as viral latency at the cellular level

Answer 9

- Typically 2-4 wks after exposure - Mononucleosis-like syndrome \*T cell proliferation to try to clear virus \*viral levels in blood drop, but virus is not completely cleared \*virus persists in lymph nodes \*microglial cells in the CNS - Typically assoc. w/R5 virus - ~80% mucosal transmission- HIV infections are due to a single virus (**founder virus**) - HIV bind to dendritic cells; taken to lymph nodes \*binding mediated by DC-SIGN \*presented to CD4 T cells by dendritic cells \*HIV internalized by DCs; spread to CD4 T cells - Loss of CD4 T cells within mucosal-assoc. lymphoid tissue (especially GALT) \*extensive depletion of CD4+ CCR5+ memory T cells in GALT +low % of CD4 T cells in GALT become productively infected and are directly killed by HIV-mediated cytolysis/apoptosis +many resting CD4 T cells are killed indirectly by pyroptosis +~80% of CD4 T cells in GALT are depleted in the 1st 3wks of HIV infection \*CD4 T cell counts return to ~normal levels in blood, but not in GALT - Virus incompletely cleared by the immune response- **viral set point**

Answer 10

- HIV stored in endocytic vesicles following entry via DC-SIGN; released via exocytosis - Productive infection of DCs; released via budding - HIV bound to DC-SIGN on surface of DC - Concentration of virions in the vicinity of CD4+ T cells - DCs present HIV peptides through MHC class II molecules to the TCR, resulting in T cell activation \*activates HIV gene transcription

Answer 11

- Highest rate of CD4 T cell death occurs during primary infection - HIV-induced cytolysis correlates w/CD4 levels on cells \*monocytes express less CD4 on their surface than T cells and are less easily killed (persisten, productive infection) - X4 viruses are more cytopathic than R5 viruses - Cell-mediated killing \*clears productively infected cells, not latently infected cells

Answer 12

- AIDS-related complex (ARC) \*lymphadenopathy, fever, weight loss, malaise \*opportunistic infections, diarrhea, fatigue - AIDS \*CD4 T cell counts \<200/microliters; viral load \>75,000 copies/ml \*AIDS-defining illnesses +HIV wasting syndrome +Kaposi's sarcoma +opportunistic infections +HIV-assoc. dementia (HAD)