what marks the first 4-8 weeks of an HIV infection?
high levels of infectious virus in plasma
what part of the immune response is responsible for clearing the initially high level of infectious virus from the plasma? what is the new level of infectious virus in the plasma called?
HIV-specific CTLs clear the plasma of infectious virus to a certain level, called the set point (cell mediated response)
what is the immune system’s next response after HIV-specific CTLs are produced?
antibodies are made against HIV env and p24 proteins (humoral response)
when is HIV transmitted easiest?
when viral loads (usually R5) are high, often during the initial infection where the infected is still unaware of the virus
what version of HIV is responsible for the primary infection? what cells does it infect?
the macrophage trophic R5 virus which infects mainly monocytes/macrophages. R5 also binds to and remains on the surface of APCs such as follicular dendritic cells (*mediated by DC-SIGN – a lectin), and is presented to CD4+ T cells which are also infected
what happens to T cell populations in MALT/GALT during primary infection?
HIV infected CD4+ cells in mucosal/gut associated lymph tissue are extensively depleted. GALT contains a high % of total CD4+ cells which are primarily memory T cells.
in HIV, when is the highest rate of CD4+ loss?
during primary infection (higher than in AIDs, but the starting point is higher)
what is the three ways that HIV can cause cell death?
direct infection-related death, HIV-induced apoptosis (affects both infected/un-infected), and CTLs clearing infected CD4+ cells
what does HIV-induced CTL cell killing correlate with?
the higher the cellular CD4+ level, the higher the likelihood it will be killed by a CTL. monocytes express less CD4+ on their surface than T cells, and are therefore less easily killed. (X4s are also mor cytopathic)
how is primary viremia tested for? what is the objective of treatment at this phase?
during the 1st couple of weeks after exposure, viral antigen such as p24 is tested for (and PCR assays quantify viral load) can b/c the antibody reponse will be undetectable at this point. at this point the goal of anti-viral therapy is minimization of viral loads for as long as possible
what precedes the antibody response in an HIV infection?
the cell mediated immune response, where productively infected cells are cleared, but not latently infected cells
what characterizes the cell mediated immune response to HIV in a primary infection?
CD8+ T cells kill infected cells, which if most are CD4+, the pt will then be more susceptible to infection and CD8+s will not be activated easily/at all
why are CD8+s generally unaffected directly by HIV infection?
CD8+ T cells produce cytokines that block binding of virus to co-receptors
what is a common reason for false negatives when testing for HIV?
if an antibody reponse is tested for, it may be too early to be detected – it can take as long as 2 wks to 6 mos after exposure to appear. meanwhile, a viral antigen test, such as the one for p24 will indicate a HIV infection
how does the antibody mediated (humoral) defense against HIV work? when does it start?
seroconversion occurs 2 weeks – 6 months after exposure. neutralizing antibodies can help prevent infection of additional cells (*bind gp120) and mediate antibody dependent cytotoxicity via NK cells. however, if antibody opsonized viruses are phagocytized, they can withstand phagocytosis and infect the phagocyte
what happens in the acute phase of HIV infection?
lots of viral replication leading to viremia, (viral antigens such as p24 should be easily testable), T cells proliferate, and try to clear the virus. since CD4+ cells are infected, the pt experiences EBV-like symptoms during this phase. serum viral levels then drop and the virus only persists in the lymph nodes and CNS microglial cells (macrophages)
what happens in the clinical latency phase of HIV?
the immune response limits productive infections, but cannot clear it. T cells and macrophages are infected and cleared, dendritic cells present HIV virus to T cells, and the cycle continues until this steady state viral load overcomes the T cell capacity
what cells can latency occur in? can these cells reactivate?
latency can occur in unstimulated cells (via pre-integration latency) and memory T cells (via post-integration latency generally). these cells can reactivate and produce more virus via transcription factors that turn on viral gene expression through interaction with the LTRs (long term repeats) = productive infection
how are pre-integration latent naive T cells created? how are they activated?
naive T cells encounter HIV virus and either become pre-integration latent cells or activated CD4+ T-cells which are activated by further exposure to the antigen, at which point it will start making virus and eventually lyse.
what happens to activated CD4+ T cells when infected by HIV?
HIV integrates into activated CD4+ T cells which either produce virus until they die of lack of plasma membrane or they go into post integration latency
what happens to resting memory CD4+ T cells when infected by HIV?
resting memory CD4+ T cells encounter HIV virus and either become pre-integration latent cells or activated CD4+ T-cells which are activated by further exposure to the antigen, at which point it will start making virus and eventually lyse.
what is the long term reservoir for HIV?
post-integration latent CD4 T cells
what are some viral reservoirs?
extracellular virus particles trapped on follicular dendritic cells, persistently infected macrophages, and latently infected memory CD4+ T cells carrying integrated HIV DNA
what is the half life of free HIV virus in the plasma?
4-5 min
what is the half life of a productively infected CD4+ T cell?
~ 1 day
what is the half life of a pre-integration latently infected resting CD4+ T cell?
~6 days
what is the half life of HIV virus on follicular dendritic cells?
~15 days
what is the half life of HIV infected macrophages?
15 days
what is the half life of a post-integration latently infected resting CD4+ T cell?
~43 months
what characterizes the transition to AIDs?
progressive decline in CD4+ T cells and increased susceptibility to co-infections and opportunistic infections
what is the cycle between T cells fighting HIV and immune system function as the progression into AIDs occurs?
virus replicates in activated CD4+, CTLs clear infected CD4+s, CD4+ levels drop, X4 HIV variants which are more cytopathic appear later and contribute to the CD4+ drop, resultant immunosuppression leads to opportunistic infections, T cells are stimulated and resting T cells are activated = more virus is made
what is ARC? when does it present?
AIDs-related complex, consisting of lymphadenopathy, fever, weight loss, and malaise. it is seen when the pt’s CD4+ count is around 500-200
when is a pt said to have AIDs? what are some AIDs-defining illnesses?
an individual is said to have AIDs when their CD4+ count is less than 200/ul. AIDs defining illnesses such as HIV wasting syndrome, kaposi’s sarcoma (HH-8), opportunistic infections (candidiasis), and HIV-associated dementia (HAD) are AIDs-defining illnesses
what are considered viral AIDs defining illnesses?
herpesviruses; HSV (chronic ulcers, bronchitis, pneumonitis, or esophagitis), CMV (retinitis; other than liver, spleen or lymph nodes), HHV8 (Kaposi’s sarcoma), EBV (Burkitt’s lymphoma, B cell lymphoma, hairy leukoplakia) and JC virus which causes progressive multifocal leukoencephalopathy
what are considered bacterial AIDs defining illnesses?
mycobacterium avium-intracellulare complex (disseminated), mycobacterium tuberculosis (extrapulmonary), and salmonella septicemia
what are considered fungal AIDs defining illnesses?
candidiasis (oral & esophageal), disseminated histoplasmosis, disseminated coccidioidomycosis, disseminated cryptococcosis (meningitis), pneumocystis jiroveci (carinii) pneumonia
what are considered protozoan AIDs defining illnesses?
cryptosporidiosis (chronic, intestinal), isosporiasis (chronic, intestinal), toxoplasmosis (brain)
what is the ideal HIV vaccine?
protection from infection via a broadly reactive neutralizing antibody binding to gp120
what are current realistic goals for HIV vaccines?
induction of a T-cell mediated response, limitation of viral replication & initial destruction of CD4+ cells, delay progression to AIDs and delay initiation of anti-retroviral therapy
what are some obstacles in developing an HIV vaccine?
lack of specific immune response understanding, lack of broadlly specific neutralizing antibody, early T cell latency, lack of safe attenuated virus, and not enough pharmaceutical interest
how is lack of understanding of the immune response an obstacle in developing an HIV vaccine?
neutralizing antibody, CD8+, CD4+, and mucosal immunity roles need to be better defined
how is lack of a neutralizing antibody an obstacle in developing an HIV vaccine?
it is difficult to find a neutralizing antibody with broad specificity for all HIV clade variations and also because of the high mutation rate
how is early latent T cell infection an obstacle in developing an HIV vaccine?
this leaves only a short amount of time to clear the virus before a chronic infection is established
what were the initial strategies for induction of humoral immunity?
most initial studies with subunit vaccines targeted gp160 (uncleaved envelope polyprotein) or gp120 with the goal of inducing an antibody reactive against different HIV variants. this antibody would inhibit HIV grown in immortalized T cell lines but not in primary isolates tested in primary peripheral blood monocytes (neutralizing antibodies raised against vaccine virus did not protect against other isolates – therefore a more broadly reactive neutralizing antibody is needed)
what do newer HIV vaccine approaches include?
newer HIV vaccine approaches include CMI in combination with humoral. gene therapy is also being investigated where DNA vaccines could be introduced to inhibit replication (to prime immunity) and viral vectors (adenovirus/canary pox) expressing HIV viral proteins would then used (boosting immunity)
what could result hypothetically from a strong T cell induction via a T cell vaccine if administered at initial HIV infection (CMI approach)?
the viremia peak titers could be decreased (and thus set point), the early loss of CD4+ could be decreased, and transmission would be minimized -> progression to AIDs would be slowed
what HIV proteins tend to be targeted in gene therapy?
regulatory protiens like vif, p17 (matrix protein), RT, env, CXCR4, and a cellular protein that tat interacts with
what do ribozymes targeted against HIV do?
these ribozymes are designed to cleave tar/env sequences
what HIV gene segments are targeted by siRNA?
these short dsRNAs trigger degradation of homologous sequences such as rev, tat, and nef
what do mutant forms of vif or vpr introduced via a viral vector do in terms of HIV activity?
mutant vif or vpr inhibit oligomerization of regulatory proteins and prevent formation of the active protein complex
what does the mutant form of CCR5 introduced via a viral vector do in terms of HIV activity?
the mutant form of the CCR5 gene decreases the surface expression of this co-receptor, partially inhibiting infectivity of R5 HIV
what can protease inhibitors do if used as agents of gene therapy for HIV?
protease inhibitors can block processing of gag, gag/pol polyproteins and gp160
what are some problems and limitations with HIV gene therapy?
strategies dependent on homologous HIV sequences (ribozymes/siRNA) are vulnerable to viral resistance (through point mutation), alteration of host gene function can have detrimental side effects, and most approaches have only been tested in vitro
what is an example of gene therapy being used to target HIV?
a U Penn trial was done where T cells were removed from HIV+ pts, infected with viruses containing no viral proteins and only some regulatory sequences & an antisense sequence that targets the env gene. e. the altered T cells are resistant to infection with HIV; they will be able to survive & repopulate T cells killed by the virus. this has been shown to drop viral loads and increase T cell counts in 4 out of 5 pts