trimethaprim sulfa for PCP, macrolide for M. avium, isaniazide for TB
Virus levels
very high during acute seroconversion (up to 1 million per mL), then drops to a set point
drops because of CD8+ host immune responses (antibody dependent cellular toxicity)
drop is not because of antibodies antibody levels do not correlate to set point, and antibodies do not neutralize
CD8+ levels are directly proportional to the set point of virus
levels of virus vary in different individuals and determine both the speed of CD4 T-cell loss and estimated survival time
host immune response and HIV destroy each other, so high levels of one produces low levels of the other
How does HIV escape the immune system? Six Methods
(1) Host proteins are contained in the virion
this may cause the immune system to mistake it for host tissue
(2) Neutralization domains may be hidden
viral receptor binding domains are exposed only when the virus binds
(3) Rapid evolutionary adaptation
"escape mutations" to evade immune or pharmacological pressure
(4) Latency
not well understood allows virus to be maintained even when there are no particles in serum
(5) nef
reduces expression of MHC type I, so no viral proteins are presented (not enough decrease to activate NK cells)
(6) Immunosuppression
decrease in number and function of CD4 cells
decrease in number
fewer CD4+ cells made from precursors in bone marrow, depressed thymus function, more apoptosis in the lymph nodes (due to env or tat), virus-induced cytolysis in the serum (primarily of naïve T-cells; normal people have naïve:memory of 1:1, HIV patients 1:5)
decrease in function
not well understood AIDS patients do not allow CD8 proliferation to antigen (anergy)
History of the Disease
1981
disease discovered in very sexually active homosexual men (more than 1000 partners)
uncertain if it could be transmitted to women
1982
disease discovered in hemophiliacs factor IX and VIII purified from tens of thousands of donors
90% of transfused hemophiliacs got the disease
1983
virus discovered by Montegnier, then Gallo and Levy the next year agreed to call it HIV
1984
antibody tests become available, produces a huge commercial struggle between (France and the US)
France delays using US test for blood-thousands infected
1985
all blood donations screened for HIV
1987
first antiviral drug (AZT) becomes available nucleoside reverse transcriptase inhibitor
decrease in mortality starting at 12 weeks, but eventually no better than untreated (RT mutates to be resistant)
Therapies for HIV
(1) Reverse Transcriptase Inhibitors
nucleoside (AZT) and non-nucleoside (nevirapine) RT inhibitors
cause decrease in viral mRNA, but back up in a few days
usually a point mutation in RT can allow the virus to avoid the drug resistant virus already present when drug is given
(2) Protease Inhibitors
more active than RT inhibitors, since there is more than one protease
however, virus eventually mutates to evade host response (stepwise emergence of resistance)
if stop drug, wild type grows out, but provirus is still somewhere in body
(3) HAART (Highly Active Antiviral Therapy)
kill potentially infected cells
see two-phase decay in plasma RNA (some infected T-cells turn over faster than others)
however, even if there are no infectious particles, some cells will still be latently infected.
There will thus be a reservoir of cells ready to produce more HIV ("resting memory cells")