December 1 2015 PSIO 431 Assignment 7 Immunology of AIDS Use the notes the textbook and you can find plenty of up to date info on new treatments by doing a quick search remember to cite your references 1 Explain how allelic variation in people has allowed some people to be exposed to HIV many times without becoming infected and progressing to AIDS 1 point There is a finding that CCR5 delta32 herterozygosity is associated with both reduced susceptibility to HIV infection as well as a reduced rate of disease progression following infection CCR5 is a commonly used co receptor that HIV uses in order to enter target cells In individuals with the genetic mutation of having CCR5 delta32 they are able to be repeatedly exposed to the virus but not become infected because the virus isn t able to enter the cell As for people who are infected with HIV but don t progress to AIDS these people are called elite controllers and about two thirds of them have the HLA B57 allele They make effective CTLs to HIV peptides that are presented in HLA B57 and there seems to be a good correlation between HIV specific CTL counts and the prognosis Allelic variation has allowed for some individuals to have this mutation and be able to be exposed but uninfected with HIV AIDS 2 What role do antibodies play in fighting off HIV infection Explain 1 point Because HIV is a virus antibodies that patients make are not protective However they do bind to the virus but they do not block attachment to and infection of T helper cells There are neutralizing epitopes on the surface of the virus but they are shielded by carbohydrates and are not readily available to B cells Also normally if a patient does make neutralizing antibody the virus quickly mutates and escapes 3 How does HIV infect cells and which cells does it infect 2 points When the HIV virus enters the body it attaches to a DC SIGN on a dendritic cells and uses the dendritic cell in order to get into the lymph nodes where T helper cells are HIV then binds by its gp120 to the CD4 molecule on T helper cells This creates a conformational change in gp120 which allows it to now bind a co receptor either CCR5 or CXCR4 This binding changes the conformation of the gp41 that is associated with gp120 exposing an extremely hydrophobic region that actually melts away the T cell s membrane allowing the cell and the virus to fuse The virus then injects its core into the cell activate its reverse transcriptase and make a dsDNA copy of its RNA The DNA moves into the nucleus and with the help of viral integrase it is inserted into a break in the host cell s DNA as latent virus HIV primarily infects cells with CD4 molecules on them T helper cells but macrophages fibroblasts T lymphocytes B lymphocytes NK cells dendritic cells hematopoietic stem cells endothelial cells microglial cells and gastrointestinal epithelial cells are the primary targets for HIV infection Klatt E 2015 4 Name two reasons why HIV is such a hard virus to kill i e ways that it can evade the immune system 2 points One reason it is so hard to kill is because reverse transcriptase is extremely error prone and doesn t have the ability to proofread It makes mistakes roughly once in 100 000 bases meaning that infected people have many variants of the virus in their body This makes it hard to target and kill Another reason HIV it s so hard to kill is because it uses our dendritic cells in order to get to the lymph nodes and bind to our T helper cells It hijacks our immune system so killing the virus would be hard because we have only a certain amount of T helper cells that are able to help fight it off before there aren t enough in our body to keep us from getting sick from other things as well We become immunocompromised and directly killing the virus would in turn kill our T cells as well 5 What role does DC SIGN play in enhancing HIV s ability to infect human cells 2 points DC SIGN is a lectin on dendritic cells which HIV adheres to and uses the dendritic cell as a Trojan horse to hitch a ride and get to the lymph nodes where T helper cells are It plays a role as the first step to HIV infecting human cells 6 There are 2 kinds of reverse transcriptase inhibitors enzyme inhibitors and nucleoside analogs How does each inhibitor drug function to prevent reverse transcription of the viral RNA into DNA 1 point Nucleoside analogs also referred to as NRTI are competitive inhibitors and chain terminators and they are believed to inhibit viral replication by several mechanisms either by competitive inhibition of the viral polymerase or by DNA chain termination Antiretroviral Agents The other drug is an enzyme inhibitor also referred to as non nucleoside NNRTI which bind a hydrophobic pocket on the enzyme that changes the conformation and the activity of the catalytic site 7 Give an example of a small peptide or mimatope something that looks like something else used to treat HIV and briefly explain how it functions 1 point One small peptide that is used to treat HIV is Enfuvirtide which is a small peptide fusion inhibitor It binds to a part of gp41 so that it isn t able to change conformation to fuse the viral membrane with the helper cells By doing this it works to stop HIV from entering CD4 T helper cells Citations Antiretroviral Agents Nucleoside Analogues n d Retrieved December 2 2015 from http livertox nih gov NucleosideAnalogues htm Klatt E 2015 Pathology of AIDS Version 26 Latest revision 2004 ed p 12 Savannah Utah Mercer University School of Medicine Savannah Cohen Z Fall 2015 Immunology of AIDS In Immunology Marmor M Hertzmark K Thomas S M Halkitis P N Vogler M 2006 Resistance to HIV Infection Journal of Urban Health 83 1 5 17 http doi org 10 1007 s11524 005 9003 8