Cellular immune control of Human Immunodeficiency Virus (HIV) Dr. Ali Jalil Ali College of pharmacy

What is HIV? HIV: Human Immunodeficiency Virus Group IV: 2 copies of +ssRNA genome, RT Family: Retroviridae Genus: Lentivirus Causes Acquired Immunodeficiency Syndrome (AIDS)

Stages of HIV infection 3 phases: acute, latent (asymptomatic) and AIDS Alimonti JB, Ball TB, and Fowke KR. (2003). J. Gen. Virol. 84, pp – 1661.

Stage I: Acute phase Infected via transfer of body fluids from HIV-infected to uninfected person Rapid viral replication after infection Increase in HIV viral load Decrease in CD4+ T-cell counts in the bloodstream ~28 days post infection: CD8+ CTL response reduces viral load to a lower level Leads to latent phase

Stage II: Latent (asymptomatic) phase Normally can last 2 – 10 years Due to immune system response: Slight recovery of CD4+ T-cell counts Occurrence of HIV-specific antibodies Help maintain HIV viral load at a lower plateau Patient is asymptomatic but infectious CD4+ cells are gradually destroyed by HIV in lymphatic organs, especially in the gut Progressive loss of CD4+ T-cells lead to AIDS

Stage III: AIDS CD4+ T-cells drop to <200 cells/mm 3 in the blood, leads to the onset of AIDS AIDS is characterized by: APC dysregulation Decrease in HIV-specific CD8+ CTL Decrease in HIV-specific Abs Sharp increase in HIV viral load Susceptibility to a variety of fatal opportunistic infections

Loss of CD4+ T-cells Why is the loss of CD4+ T- cells so devastating for the immune system? CD4+ T-cells (T H 0) help direct appropriate immune responses against pathogen (T H 1 or T H 2) Loss of CD4+ T-cells lead to dysregulation of immune system and an inability to fight invading pathogens The human immune system –

HIV Cellular Pathogenesis

Laboratory Diagnosis Serology is the usual method for diagnosing HIV infection. Serological tests can be divided into screening and confirmatory assays. Screening assays should be as sensitive whereas confirmatory assays should be as specific as possible. Screening assays - EIAs are the most frequently used screening assays. The sensitivity and specificity of the presently available commercial systems now approaches 100% but false positive and negative reactions occur. Some assays have problems in detecting HIV-1 subtype O. Confirmatory assays - Western blot is regarded as the gold standard for serological diagnosis. However, its sensitivity is lower than screening EIAs. Line immunoassays incorporate various HIV antigens on nitrocellulose strips. The interpretation of results is similar to Western blot it is more sensitive and specific.

Western blot for HIV antibody There are different criteria for the interpretation of HIV Western blot results e.g. WHO, American Red Cross. The most important antibodies are those against the envelope glycoproteins gp120, gp160, and gp41 p24 antibody is usually present but may be absent in the later stages of HIV infection

Therapy Reverse Transcription Inhibitors Nucleoside RT inhibitors e.g. Zidovudine or AZT (azidothymidine) Non-nucleoside RT inhibitors e.g. nevirapine (Inhibit RT) Protease inhibitors (proteases cleave precursor proteins into proteins that are needed for virion assembly) Integrase inhibitors (integration of provirus in the cell DNA e.g. ritonavir) Entry/Fusion inhibitors e.g. enfuvirtide HAART (Highly active anti-retroviral therapy) – combination Problems: Anemia Virus in brain Antigenic variation BBB – not penetrated by drugs High costs.