BL.2.10: Immunology of AIDS, Lymphoid neoplasms 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 â–ºTh (CD4+) cells fall below 200/μL of blood, it’s AIDS.
Name the virus that causes AIDS, and its classification.
HIV-1Non-transforming retrovirus: an RNA virus that carries no oncogene, and reproduces itself by copying its RNA into DNA by means of its enzyme, reverse transcriptase.
Discuss the origin of the AIDS virus and the origins of the current epidemic.
It is thought that HIV-1 evolved recently from SIV, perhaps as recently as the 1940s and possibly in Zaire (now the Democratic Republic of Congo).Seroepidemiology indicates that this disease moved to the Caribbean in the mid-60’s (perhaps brought there by Cuban soldiers returning from Angola) and to Europe a bit later. The epidemic in the USA, which started in New York, Los Angeles, and San Francisco, was probably brought in by homosexual men who had vacationed in Haiti.
Identify the approximate number of cases in the U.S. and in the world, and discuss the rate of change in incidence.
By 2004 AIDS was the 5th leading cause of death in the world, the 4th in developing countries. So far, 28 million have died. In the USA, the CDC counted 982,000 cumulative cases of AIDS by the end of 2006, of whom 546,000 had died. However, â–ºabout 800,000 people are living with HIV in the United States, and 25-40% don’t know it.Worldwide, 33.4 million have it.
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 virus enters the body, it may adhere to a lectin on dendritic cells called DC-SIGN2. 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. â–ºHIV 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, â–ºone of the chemokine receptors, CCR5 or CXCR4. When a person is first infected, almost all the virus is CCR5-tropic.In turn, 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. 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 complex moves into the nucleus. Helped by a viral integrase, the DNA is then inserted randomly into the host cell’s DNA as latent virus. We know little about how latency is regulated, or whether it is harmless to the cell.As viruses bud en masse from the infected cell, they tear so many holes in the membrane that the cell dies.
Distinguish between the roles of Th1 and Th2/Tfh in the progression of HIV infections.
The antibody that patients make is obviously not protective. Many scientists are beginning to think that most people with HIV infection have a Th2/Tfh-dominated helper T cell response. Perhaps the way HIV loads into DC has something to do with this, polarizing the DC so that it favors Th2/Tfh over Th1. â–ºIf patients made more Th1 they might stimulate more CTL, and do better. There is evidence that HIV positive patients who make good CTL against HIV antigens have an improved prognosis.
Discuss the types of infections seen in AIDS patients, and provide an immunological basis for this spectrum.
The infections seen in AIDS are primarily of types that require T cell-mediated immunity, as might be expected given the virus’ primary target. CMV, HSV- simplex and zoster, fungi including Candida albicans and Pneumocystis jirovecii.Protozoan infections, such as Toxoplasma, Cryptosporidium, and Isospora are very serious.Infections with opportunistic intracellular bacteriaâ_¯ï£§usually Mycobacterium avium- intracellulare, or MAI, and more and more commonly, M. tuberculosisâ_¯ï£§are frequent.
Discuss possible reasons for which the total number of CD4 cells in AIDS patients decline.
Since CD4 cells are originally turning over every 3 days, with time, CD4 cells are gradually lost; it looks 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). An accelerating fall in this ratio, or an absolute CD4 count below 400/μL, are poor prognostic signs. When the immune system can no longer cope, opportunistic infections take hold.
Discuss reasons for the apparent ineffectiveness of antibody in HIV infection.
A very significant behavior of the virus is this: when the virus is replicating, gp120 is made early, and it becomes inserted into the cell’s plasma membrane. â–ºThis 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 easily explain why the antibody patients make seems to be useless.
Define and discuss “elite controllers.”
65% of ‘elite controllers,’ who harbor HIV but retain normal immune function for many years, are HLA-B57. They make more, and more diverse, CTL against HIV peptides than people with other HLA alleles. New treatments have extended life expectancy remarkably.
Describe the laboratory diagnosis of AIDS.
The most common test is for antibody to HIV. â–ºAntibody 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.
Discuss the prospects and problems of AIDS vaccine development.
a large vaccine trial fizzled (May 2003); it produced good antibody responses but did not, overall, decrease infection rates. Why? Because we need a vaccine that can preferentially stimulate Th1 cells and CTL; the current vaccines seem to be best at inducing antibody responses, and antibody doesn’t protect very well (otherwise seropositive people wouldn’t get sick). The key epitope on HIV seems to be well-concealed within the gp120/gp41 complex and almost invisible to B cells.However, it has been shown several times recently that a small amount of the antibody some people make is neutralizing; analysis of the recognized epitopes, it is hoped, could lead to a new ‘designer’ vaccine. Merck has provided a proof-of-concept epitope made this way. This is encouraging, because in 2007 Merck reluctantly had to close the 4-year ‘Step’ trial of an adenovirus-based vaccine with 3 HIV genes engineered in, which was just plain was not protecting high-risk people from infection. In 2009, a large trial (called RV144) in Thailand reported significant protection for the first time, though the effect was disappointingly modest.
Describe what it means for a lymph node to be effaced.
When a lymph node is involved by non-Hodgkin lymphoma its normal architecture is either partially of completely effaced depending on whether the lymphoma occupies part of the lymph node or all of it. Effaced can be equated with replaced and obliterated. Lymph nodes are also effaced in Hodgkin lymphoma.
Discuss the two main patterns seen in non-Hodgkin lymphoma in terms of what they look like and what cell types (B-cell, T-cell) are associate with each pattern.
Diffuse: Many benign B-cells, and all T and NK-cells are present in their lymph node and extra- nodal niches in diffuse sheets.Follicular: follicular non-Hodgkin lymphomas are composed of cells with morphologies similar to benign germinal center cells and these cells usually form germinal center-like structures. B cells.
Discuss why there are so many different B-cell and T-cell neoplasms described in the WHO classification system.
Under the WHO 4th Edition classification system B lymphoblastic leukemia/lymphoma is divided into B lymphoblastic leukemia/lymphoma, not otherwise specified and B lymphoblastic leukemia/lymphoma with recurrent genetic abnormalities. There are a number of recurrent genetic abnormalities in the second category that are associated with fairly distinctive clinical or phenotypic properties, or have prognostic implications. This probably applies to T cells too.
