Human Immunodeficiency Virus

Acquired Immunodeficiency Syndrome or AIDS, caused by Human Immunodeficiency Virus (HIV), is the greatest challenge to public health in modern times. Initial reports of this syndrome came from New York and Los Angeles in 1981 when there was an outbreak of two rare diseases, Kaposi’s sarcoma and Pneumocystis Carinii, among young homosexual adults. The virus was later isolated by the Pasteur Institute in Paris and The National Institute of Heath in the USA in 1983 and 1984 respectively. The International Committee on Virus Nomenclature gave the virus its generic name, Human Immunodeficiency Virus, in 1986.

Epidemiology

The World Health Organization estimates that about 33.2 million people are living with HIV worldwide. Sub-Saharan Africa is the most highly affected with one in every three people infected with HIV. Approximately 4 million people are infected in the South and Southeast Asian region while 1.6 million people are affected in Europe and Central Asia. The modes of transmission are sexual and via blood and blood products. There are two viral types, HIV 1 and HIV 2, with numerous sub-groupings.  They are M, N, O for HIV 1 and A to H for HIV2. The last five decades have revealed the emergence of numerous subtypes, sub-subtypes and circulating recombinant forms (CRF). There are a minimum of 9 different subtypes of HIV1 and over 20 CRFs have been discovered within the M group. This is the largest subtype contributing to the AIDS pandemic. The HIV1 subtypes C and A predominate globally.

Human Immunodeficiency Virus

HIV is an enveloped retrovirus whose genome is composed of two identical strands of RNA. The nucleocapsid also contains the reverse transcriptase and the integrase enzymes.  The viral RNA contains the following structural genes which code for p55, p100 and gp 160 respectively.

  • gag 
  • env 
  • pol

These are further broken down into various proteins such as p100 which forms protease, endonuclease and reverse transcriptase. Gp 160 forms gp 120 and gp 41 and the glycoprotein 120 (gp120) is essential for viral entry into the host cells.S

Stability of the virus

 The virus can survive up to 15 days at room temperature and at 37º C for 10 to 15 days. HIV can be deactivated by

  • Heat : autoclave or hot air oven
  • 2% Gluteraldehyde
  • 10000 ppm of hypochlorite
  • 70% alcohol

Therefore, HIV, like other enveloped viruses, is an unstable virus and can be easily deactivated utilizing disinfectants. But, it is critical to remember that majority of disinfectants get deactivated in the presence of organic matter.

Newer developments in the pathogenesis of HIV infection

Viral replication primarily takes place in the lymphocytes. The virus has specific receptors and co- receptors through which it attacks the cells. These are the CD4 receptors, the CCR5 and CXCR4 receptors which are present on the lymphocytes and macrophages respectively. The binding of gp 120 with the CD4 receptors and the co-receptors is required for the fusion of the viral and cellular membranes. There is evidence that gp 120 potentiates polyclonal activation of the B cells, which differentiate into immunoglobulin producing cells and also activates the complement. This leads to the formation of immune complexes which are incapable of destroying the virus. In fact, they shield it from the destructive effects of other immune mechanisms. Thus gp120 protein has several properties that affect the reaction of the immune cells to the virus by altering the immune response thereby facilitating the escape of the virus from the effector arm of the immune system.

It has recently been discovered that some people have been exposed to the HIV virus repeatedly without becoming infected. Such people may harbor deactivated copies of the CCR5 gene which is a co-receptor for viral entry into the macrophages. This prevents establishment of infection as macrophages serve as cells in which the virus can enjoy a latent existence.

Antiretroviral drugs: Drug therapy in HIV is always combined. Various classes of drugs are used as a multi-pronged approach to keep the viral copies in the blood at a minimum. Therapy is monitored by performing viral load assays at regular intervals to determine the effect of therapy and the emergence of resistance.

  • Nucleoside/nucleotide analogs: Zidovudine was the first drug of this class. This has been followed by many others like abacavir, lamivudine, stavudine, emtricitabine etc. Lactacidosis and disorders of lipid metabolism are the long term side effects of this group of antiretroviral drugs.
  • Nonnucleoside reverse transcriptase inhibitors: Neviprapine, delaviridine, efavirenz are some of the non nucleoside reverse transcriptase inhibitors (NNRTIs). One important fact to be noted for this group of drugs is that resistance to one drug of the group leads to selective resistance to the rest of the group. Therefore, before beginning a regimen containing NNRTIs, it is important to assess the patient’s motivation and discuss ways to manage any possible side effects.
  • Protease inhibitors: Several protease inhibitors are available for use as combined therapy such as indinavir, amprenavir, ritonavir, sequanavir etc. The majority of protease inhibitors are metabolized in the cytochrome P450 system and show drug interactions with other medications metabolized by cytochrome P450.  This requires alteration of the dosage for the protease inhibitors. 
  • Fusion Inhibitors: Enfurvitide (Roche/Trimeris) is a fusion inhibitor which was approved by the US FDA in 2003. It can be used in advanced cases of adult as well as pediatric infections. This drug binds to the gp41 of the HIV envelope thus preventing the fusion of the virus with the host cell membrane. 
  • Chemokine co-receptor antagonists: The first agent to be approved in this class of drugs is Maraviroc (Pfizer). It binds to the co-receptor CCR5  blocking the entry of the virus into the CD4 cells. This drug is a substrate of the cytochrome 450 enzyme system (CYP3A) and possesses interactions with numerous medications such as ketoconazole, carbamazepine and other antiretroviral drugs.
  • Integrase inhibitors: Raltegravir (Merck) is the US FDA approved drug in this group. It inhibits the integration of the reverse transcribed HIV DNA into the host cell chromosome.