Practice Questions HIV/HTLV-1

The virus responsible for causing acquired immune deficiency syndrome (AIDS) is classified as a retrovirus. Many of the drugs used to treat human immunodeficiency virus (HIV) infection take advantage of a unique sequence of events involved in the replication of retroviruses. In order for HIV to replicate, which of the following steps must occur first? a. The viral RNA must be converted to DNA b. The viral RNA must be degraded c. New viral RNA molecules must be synthesized by the viral RNA polymerase d. The host cell must synthesize reverse transcriptase e. A DNA polymerase must be synthesized from the RNA template

1. The correct answer is "a". HIV carries reverse transcriptase in the virion which copies the RNA genome into DNA. See #4 below.

There are also a significant number of HIV-infected individuals who never become sick, never experience a decline in their CD4 counts, and never develop high plasma loads of viral RNA. The reason for this seems to be the presence of host genetic mutations that render them resistant. Mutations in which of the following genes might provide resistance to HIV infection? a. CXCR4 b. CCR5 c. Mac-1 d. SDF-1 e. Interleukin-8

CCR5 is necessary for HIV entry into the host cell. CCR5 is expressed by macrophages, dendritic cells, and CD4 T cells. It is thought to be the major co-receptor for establishing primary infection, since individuals who are homozygous for a mutation in CCR5 appear to be resistant to infection by HIV. For example, the CCR5-Delta32 deletion mutation seems to confer resistance against HIV-1 by blocking its attachment to CCR5 so that HIV cannot gain entry to the cell. Development of drugs directed at chemokine receptors is thus an active area of research. CXCR4 is the other major co-receptor for HIV. Lymphotropic HIV uses CXCR4 found on T cells and requires a high density of CD4 on the cell surface. CXCR4 also binds the CXC-chemokine stromal-derived factor-1 (SDF-1) as a co-receptor. Both co-receptors are G-coupled proteins with 7 transmembrane spanning domains.

The human immunodeficiency virus (HIV) shows extensive genetic variation and undergoes rapid evolution. The rapid replication of HIV, coupled with genetic variability, leads to the generation of many variants of HIV in a single infected patient in the course of an infection. Thus, HIV can rapidly develop resistance to antiviral drugs. When antiviral drugs are administered, variants of the virus that carry mutations conferring resistance to their effects emerge and expand until former levels of plasma virus are regained. Resistance to some of the protease inhibitors appears after only a few days. This remarkable variability, which was first recognized in HIV, has since been proven to occur in other lentiviruses. Which of the following is the most likely mechanism for these phenomena? a. Gene conversion b. Hypermutability c. Gene duplication d. Antigenic shift e. Antigenic drift

The correct answer is "b". The hypermutability of HIV, which mutates at a rate 1,000,000 times as great as that of eukaryotic DNA genomes, is important to the pathogenesis of HIV. The high error rate of HIV reverse transcriptase in vitro translates to approximately 5 to 10 errors per HIV genome per round of replication in vivo. This high error rate suggests that misincorporation by HIV reverse transcriptase is, at least in part, responsible for the hypermutability of the AIDS virus. Researchers hope that our understanding of the process may provide a basis for the systematic construction of antiviral nucleosides. In gene conversion, DNA segments are copied so that one sequence replaces sequences in another gene on the same chromosome. Studies of the sequences of different alleles have shown that the same sequences are found within several genes on the same chromosome, providing evidence for gene conversion. Gene duplication is the creation of an extra copy of a gene. This is a key mechanism in evolution. Once a gene is duplicated, the identical genes can undergo changes and diverge to create 2 different genes. Duplications typically arise from an event termed unequal crossing-over that occurs between misaligned homologous chromosomes during meiosis. Antigenic shift is the appearance of a new assortment of genes. This type of reassortment happens rarely and can be devastating, since shift produces a virus strain with a combination of surface antigen proteins to which the human population will have little or no immunity. Antigenic drift is caused by point mutations in the genes of microbes, such as the influenza virus. Every 2 to 3 years, a variant arises with mutations that allow the virus to evade neutralization by antibodies in the population. As new variants appear, they replace the previous variant so that within about 4 years, a given individual can be re-infected with an antigenic variant that has been gradually generated by infection of other individuals. This results in local epidemics.

During a medical check-up for a new insurance policy, a 60-year-old grandmother is found to be positive in the ELISA screening test for antibodies against HIV-1. She has no known risk factors for exposure to the virus. Which of the following is the most appropriate next step? a. Immediately begin therapy with azidothymidine b. Perform the screening test a second time c. Request that a blood culture be done by the laboratory d. Tell the patient that she is likely to develop AIDS e. Test the patient for Pneumocystis jiroveci infection

The correct answer is "b". The standard screening test was done BY ELISA but these are not 100% accurate for sensitivity and specificity. The newer generation of tests detects not only antibody to HIV but the antigen p24. In this case, a second blood sample would be collected for retesting. A NAT would be used to confirm the initial test.

You have a 25-year old female patient in your office who had just discovered that her sex partner is HIV positive. They have been sexually active within the past week and she is on birth control pills so they have not been using condoms. You ordered a blood test (serology/antibody only) for HIV that came back negative. She is also negative for other sexually transmitted diseases. Which one of the following statements is TRUE for this patient? A. Since the HIV test came back negative, she is not infected and there is no need to test her again B. The risk of HIV transmission through heterosexual route is so remote that this patient should not be concerned any more C. She is potentially in the window period of acute infection, so the negative antibody test does not rule out HIV infection D. Since she is using birth control pills, she should not be concerned because HIV is inactivated by birth control pills E. The antibody test can be repeated in a week to definitively rule out infection as she will have had sufficient time to produce detectable levels of antibody

The correct answer is "c". Since she has been sexually active within the past week, she could have been infected very recently. In this situation, an antibody only test would most likely not be positive yet as she has not had time to develop detectable antibodies post infection. Early in the acute infection process, circulating viral nucleic acid and p24 antigen are detectable before antibody. She should be tested with an assay that is better at detecting acute infection such as an antibody/p24 antigen combination assay or a nucleic acid amplification test (NAAT). A is incorrect as explained in the explanation for why C is correct. B is incorrect as heterosexual intercourse is an effective means of transmission of the virus. D is incorrect as birth controls are not effective in preventing HIV transmission.

A 42-year-old HIV-positive male presents to his primary care physician with an ongoing "rash". He is not currently on an antiviral regimen. His most recent CD4 T cell count was 180/mL. Physical exam reveals a frail appearing male, who appears older than his stated age, with erythematous and purple nodules on his face, trunk, and back. What is the appropriate treatment? a. Topical steroids b. Oral antibiotics c. Antiretroviral therapy d. Surgical excision e. Topical retinoic acid

The correct answer is "c". This patient is presenting with Kaposi's sarcoma. This is a systemic disease caused by human herpes virus 8 (an oncogenic virus). It can present with cutaneous lesions and is considered an AIDS-defining illness, seen with CD4 counts < 200 cells/mL. As such, the appropriate treatment is highly active antiretroviral therapy (HAART).

An HIV-positive patient asks you if you can tell him the chances of him progressing to symptomatic AIDS. Which one of the following tests would be most useful? a. CD8 lymphocyte count b. HIV antibody test c. HIV RT PCR d. Neopterin e. HIV p24 antigen

The correct answer is "c". Viral load is typically used to monitor response to therapy. The viral load at a patient's set point is also a prognostic indicator of how quickly they might progress to AIDS. Generally, higher viral load set point during virus latency is associated with a faster progression to AIDS.

You wish to develop a retroviral inhibitor as part of your project at the Flumax Pharmaceutical Company. Of the many approaches that you might try, one that may have some success would be to target elements that are required for the replication cycle of the viral particle. Some of these targets might be a. Integrase and reverse transcriptase, which are carried in the virion b. Integrase and reverse transcriptase, which are made by the host cell c. Integrase and mutase, which are carried in the virion d. Integrase and mutase, which are made by the host cell e. Integrase and reverse transcriptase, which are carried by the covirion

The retroviral life cycle begins when the virion lands on specific receptors and enters the cell, where the virion coat is removed in the cytosol. The virus particle contains two copies of an RNA molecule. One of the copies is designated the (+) strand. In addition to the (+) strand, the virion also carries into the host cell the enzyme reverse transcriptase and a non-covalently attached tRNA molecule. The enzyme reverse transcriptase has three major activities: RNA-directed DNA synthesis, DNA-directed DNA synthesis, and RNA hydrolysis. The RNA molecule that the virion brings into the cell must be duplicated for the viral life cycle to continue. The steps of this process are as follows: Using the tRNA that the virion brings into the cell, the transcriptase engages in DNA synthesis in the 5' to 3' direction. This gives a short segment of DNA that is attached to the tRNA. This DNA is termed (-) DNA. RNAase activity of the transcriptase removes RNA bases paired with the newly formed DNA. The (+) RNA strand contains repeated sequences at each of its termini. The newly formed DNA-tRNA hybrid molecule pairs with the other end of the (+) RNA strand and the RNA is reversed transcribed into DNA. Most of the (+) RNA strand that is now paired with the newly synthesized DNA is hydrolyzed by the RNAase activity of the transcriptase. The remaining small segment of RNA is used as a primer to replicate a (+) DNA strand from the (-) DNA strand used as template. Any residual RNA is hydrolyzed. The newly formed (+) DNA strand pairs with the opposite end of the (-) DNA strand and primes the synthesis of the remaining (+) DNA strand. Each end of the (-) DNA strand consists of long terminal repeat sequences termed long terminal repeats (LTR). For it to function, the formed linear DNA must travel to the nucleus and be integrated into the host genome. The integration reaction is catalyzed by the viral product integrase, which is carried in the virion along with the reverse transcriptase. The integration of the viral DNA occurs at random sites in the host genome. Integrated proviral DNA is transcribed by the host enzymes to make viral RNAs. These RNA molecules can function both as mRNA and as inserts to make more virion particles.