Immunology of AIDS Flashcards
- Explain the difference between “HIV-seropositive” and “AIDS”.
People are ‘seropositive’ if they have antibody to HIV, which is the most common way in which infection is first detected; once they get symptoms of opportunistic infections or Kaposi’s sarcoma , or their► Th (CD4 + ) cells fall below 200/μL of blood , it’s AIDS. ( Normal range: 500 - 1000/ μL)
- Name the virus that causes AIDS, and its classification
- Discuss the origin of the AIDS virus and the origins of the current epidemic.
- Identify the approximate number of cases in the U.S. and in the world, and discuss the rate of change in incidence.
INCIDENCE AND PREVALENCE. First described in 1981, by 2004 AIDS was the 5th leading cause of death in the world, the 4 th in developing countries. So far, 40 million [34 - 46] have died .
In the USA, the CDC counted 1, 160,000 cumulative cases of AIDS by the end of 20 12, of whom about 800,000 had died.
With new treatments, death rates have fallen remarkably: 38,000 died in 1996, 15,500 in 20 10 . However, ►about 1,123,000 people are living with HIV in the United States, and about 1 4 .5 % of them don’t know it.
There are 50,000 new cases a year. OraQuick , a home test for HIV antibody, was approved in May 2012. It produces only 1:5000 false positives, but 1:12 false negatives, so it should be useful but not definitive for reducing that 1 4 .5 %.
There are about 11,200 people living with HIV/AIDS in Colorado (2014 figure) . Incidence in Colorado has been falling since 1993 ; there were about 400 new cases in Colorado in 2011, and 150 deaths. About 25% of new cases were first diagnosed when they al ready had AIDS; that number must come way down.
- Define and discuss “long-term survivors” and “elite controllers” in HIV infection.
Long-term survivors are homozygous for what receptor? This means that they ___ express surface CCR5.
Elite-controllers become infected but did not progress to AIDS becuase they have the ______ allele. Why is this important?
In the years before the first HIV drug (1981 - 1987) 95% of all infected people died of tumors or opportunis tic infections.
A few were identified as “long-term survivors” (LTS). Of these, some are homozygous for a 32-base pair deletion in the gene for a chemokine receptor, CCR5 (they were CCR5 32 ). As you’ll see below, CCR5 is an HIV coreceptor. People with two CCR5 32 alleles do not express any surface CCR5; although they can be chronically infected with HIV they do not become ill. It seems probable that the infection in these people remains in DC and macrophages and does not affect helper T cells. The mutated allele occurs at a 10% frequency in Caucasians, but is very rare in other populations.
A different group of LTS were “elite controllers.” They became infected but did not progress to AIDS. Two - thirds of them have the HLA-B57 allele (correctly called HLA - B*5701) . They make effective CTL to HIV peptides presented in HLA - B57. There is a good correlation between HIV - specific CTL numbers and prognosis.
- Discuss the pathogenesis of AIDS, including target cell types, mode of entry of the virus into a cell, mode of exit, latency versus productive infection.
Antibody to HIV peaks by _____ weeks.
What is the incubation period?
► After a single exposure, infected people develop high blood virus levels (>10 5 copies/mL) that peak at about 6 weeks.
There is a loss of CD4 cells in the gut mucosa, and an associated increase in gut permeability. HIV spreads systemically. Antibody to HIV peaks by 9 weeks, whereupon virus levels fall sharply, but not to zero.
This new level is the patient’s “set point” and it seems to reflect the abilities of their immune system, rather than those of the virus. The mean incubation period (infection to AIDS ) estimated from transfusion - acquired HIV infection , where it could be most precisely timed , it was about 9.5 years without treatment.
- Discuss the pathogenesis of AIDS, including target cell types, mode of entry of the virus into a cell, mode of exit, latency versus productive infection.
When the HIV virus enters the body, it adheres to? Why?
HIV binds its envelope glycoprotein gp120 to ____ molecule on the surface of Th cells. What happens after?
What does binding to CCR5 does to the virus envelope proteins?
1- When the virus enters the body, it may adhere to a lectin on dendritic cells called DC - SIGN 1.
–> Taken up by this means it is not harmed, and thus uses the DC as a Trojan horse to get to the lymph nodes where the Th are.
2- HIV binds by its envelope glycoprotein, gp120, to the CD4 molecule on the surface of Th cells. This induces a conformational change in gp120, which allows it to now ►bind a co-receptor, one of the chemokine receptors, CCR5 or CXCR4 .
–>When a person is first infected, almost all the virus is CCR5 - tropic.
In turn, binding the chemokine receptor changes the conformation of the gp41 glycoprotein that is associated with gp120, exposing a very hydrophobic region that literally melts away the T cell’s membrane, so the cell and virus fuse.
3- The virus can thus inject its core into the cell, activate its reverse transcriptase and make a double-stranded DNA copy of its RNA. The DNA moves into the nucleus. Helped by a viral integrase, it is then inserted into a random break in the host cell’s DNA as latent virus.
We know little about how latency is regulated, or whether it is harmless to the cell. It may be that HIV goes latent in resting cells and replicates productively in activated ones . By using all three reading frames, the small HIV genome (9749 bases) encodes 9 genes: the gag , pol , and env genes that all retroviruses have, and 6 others that regulate latency and virulence. By alternative RNA splicing, and protease - mediated cleavage of 3 large precursor proteins (HIV makes its own protease) it can make 16 polypeptides .
- Discuss the pathogenesis of AIDS, including target cell types, mode of entry of the virus into a cell, mode of exit, latency versus productive infection.
HIV-infected T cells may die rapidly; become persistent virus - producers; or enter latency.
In the first case, as viruses bud en masse from the infected cell, they tears o many holes in the membrane that the cell dies.
In the early, pre-AIDS stage of the disease, the clearance rate of virus and the replacement rate of CD4 cells are incredible: ► it has been estimated that the entire population of virus is replaced daily, and CD4 cells every 3 days.
A very significant behavior of the virus is this: when the virus is replicating, gp120 /gp41 is made early, and it becomes inserted into the cell’s pl asma membrane. ► This allows fusion of the infected cell to nearby uninfected CD4 cells, and a syncytium forms. In this way the virus can spread without an extracellular phase. This could be part of the reason the antibody patients make seems to be useless. With time, CD4 cells are gradually lost; it look s like simple exhaustion of the ability to make more of them . This is commonly expressed as a falling blood CD4/CD8 ratio (the normal ratio is from ~1.5 to 3). When the immune system can no longer cope, oppo rtunistic infections take hold .
- Discuss the role of Tfh in the persistence of HIV latency and active infection.
Tfh cell can develop into a _______, which can lead to gradual dysregulation of B cells.
During the long seropositive period ► the major site of HIV persistence is memory Tfh cells in the lymph nodes. They are able to suppress viral replication but not eliminate the virus DNA from their nuclei.
**If such a cell changes to get activated by its correct antigen, it will develop into a clone of virus-producing cells. This disruption of Tfh function leads to, or is accompanied by, a gradual dysregulation of B cells, which early on can be hyperactivated, and later become exhausted so that antibody production begins to decline.
- Discuss the types of infections seen in AIDS patients, and provide an immunological basis for this spectrum.
Can it affect the brain?
What is the leading cause of death in people infected with HIV?
The most common condition is to be seropositive without symptoms, as are about a million people in the United States. After the acute infection, there is a phase of clinical latency — viral infection without symptoms — that may last years. Good therapy can keep the next stages from developing.
Next would be the development of a minor opportunistic infection (OI) like Candida albicans (a yeast) of the mouth, esophagus, or rectum. There may be fevers, night sweats, weight loss and fatigue. With the appearance of major opportunistic infections (including TB) or malignancy (commonly Kaposi sarcoma, less commonly Burkitt lymphoma or other lymphoma), or an absolute CD4 count below 200, the full - blown AIDS picture is present. This progression, as we said, is with treatment no longer inevitable.
Because the brain also has cells that can be infected by HIV, including macrophages and microglia, there is a not-uncommon late AIDS dementia complex which is terribly distressing for patients and family. It is probably the consequence of toxic cytokine release by virus - activated phagocytes .
The infections seen in AIDS are primarily of type s that require T cell - mediated immunity, as might be expected given the virus’ primary target.
- We see viral infection, including cytomegalovirus, hepatitis and especially herpes simplex and zoster.
- We see fungi, especially Candida albicans and Pneumocystis jirovecii.
- Protozoan infections, such as Toxoplasma, Cryptosporidium (which causes a sometimes - fatal diarrhea), and Isospora are very serious.
Infections with opportunistic intracellular bacteria usually Mycobacterium avium complex or MAC, and more and more commonly, M. tuberculosis are frequent.
In fact, ****TB is the leading cause of death in people infected with HIV.
High-grade, extracellular bacterial pathogens are less of a problem, possibly because the ability to make Tfh-independent antibody responses to capsular polysaccharides is preserved.
Kaposi sarcoma is a tumor of the endothelial cells lining lymphatics. It is caused by KSHV (Kapo si’s sarcoma herpesvirus,) also called HHV8 (human herpesvirus 8).
- Describe the laboratory diagnosis of AIDS.
The patient will often have made the diagnosis. The most common test is for antibody to HIV.
► Antibody is measured by an ELISA which has a certain false - positive rate, so a positive ELISA must be confirmed by Western Blot analysis, in which standardized viral protein preparations are separated by electrophoresis, blotted and fixed to nitrocellulose, and then ‘stained’ with the patient’s antibodies, which must bind to the correct viral proteins (gp120, gp41) for the test to be considered a true positive.
In richer countries, once the diagnosis is made, the virus is sequenced to see what drugs it will be susceptible to.
► Very small amounts of the virus RNA itself are now detected by the polymerase chain reaction (PCR), and this is very useful for following therapy. In patients who can be gotten down to about 50 viral particles/mL or lower and kept that low, disease progre ssion seems to be halted. But so far, in spite of the occasional hopeful news story, o nly one — the “ Berlin patient ” — h as remain ed virus - free without continuous treatment
- Discuss reasons for the apparent ineffectiveness of antibody in HIV infection.
The antibodies that patients make are obviously not protective. Though they bind to the virus, they do not block attachment to and infection of Th cells. There are neutralizing epitopes on the virus, but they are shielded by carbohydrate and not readily available to B cells. Typically, if a patient does make neutralizing antibody, the virus rapidly mutates and e scapes.
- Discuss the prospects and problems of AIDS vaccine development
HIV vaccine challenges :
- HIV exhibits tremendous global genetic diversity.
- Its immense mutational capacity allows evasion of both T and B cell immunity.
- HIV goes latent in the host genome, from which it cannot be eliminated by conventional antiretroviral drugs.
- There has been no known example of spontaneous im mune clearance, to use as the basis for data - driven vaccine design.
- Although bnAbs have been found, they are rare, only found in a subgroup, take years to develop, and are extensively hypermutated; no method exists now for induction of these Abs by im munization.
- But a lot of smart people think that they can figure out a way to make these epitopes immunogenic in everybody.
