HUMAN IMMUNODEFICIENCY VIRUSES (HIV-1, HIV-2)

Introduction HIV is a sexually transmitted, human virus. The viruses (HIV-1 and HIV-2) were recognized in the 1980s. HIV-1 is largely responsible for the acquired immune deficiency syndrome (AIDS) pandemic, while HIV-2 is mainly restricted to West Africa. In the absence of treatment, and normally after many years of infection, HIV infection damages the immune system to the point where the body cannot combat common infections and AIDS results.

Origins of HIV-1 and HIV-2 It is certain that HIV-1 and HIV-2 arrived in the human population as zoonoses. These viruses are related to a group of more than 40 simian immunodeficiency viruses (SIV), most of which has a relatively benign nonpathogenic interaction with its natural primate host. In 1999, a strain of SIV (called SIVcpz) was found in a chimpanzee that was almost identical to HIV in humans. The researchers who discovered this connection concluded that it proved chimpanzees were the source of HIV-1, and that the virus had at some point crossed species from chimps to humans.

Characteristics They belong to the lentivirus genus of the Retroviridae family. They contain two identical + single-stranded RNA molecules. HIV exhibits a characteristic cone-shaped core. HIV is enveloped “lipid bilayer derived from the host cell membrane”. The viral envelope is studded by virally encoded envelope glycoproteins: gp120 (surface unit) gp41 ( transmembrane unit)

Characteristics Other proteins in the virus particle: P17 (matrix protein), lines the inner surface of the virus particle P24 (major capsid protein), surrounds two copies of RNA P9 (nucleic acid binding protein) Protease Integrase Reverse transcriptase In the capsid Retroviral integrase (IN) is an enzyme produced by a retrovirus (such as HIV) that enables its genetic material to be integrated into the DNA of the infected cell. 

HIV Genetic Composition HIV-1 and H IV-2 have genomes about 9.3 kb in length. Structural genes  encode for products which participate in formation of functional structure of virus env (envelope): Encodes the viral envelope proteins; gp120 and gp41 gag (group associated antigen): Encodes the viral proteins p24; capsid “CA” and p17 “MA” (membrane associated matrix protein). P6 and P7 nucleocapsid proteins protect RNA from digestion by nucleases. pol (polymerase): Encodes the viral enzymes; reverse transcriptase, integrase, and protease

HIV Genetic Composition gag and pol genes cooperate to form fusion proteins which cause fusion of cells enabling HIV to pass from one cell to another thus evading the components of the immune system. gp 41 has a domain which acts as fusion protein. A protein domain is a conserved part of a given protein sequence and (tertiary) structure that can evolve, function, and exist independently of the rest of the protein chain

HIV Genetic Composition Regulatory Genes Tat (transactivator of transcription) Regulates HIV replication and accelerates viral protein production by a thousand fold. Rev (regulator of virion) Permits unspliced mRNA to leave the nucleus, it inhibits transcription of the regulatory genes while enhancing expression of the viral structural genes. Vif (viral infectivity factor) Increases viral infectivity and may be responsible for the efficient cell-to-cell transmission of HIV. Nef (negative regulatory factor) Enhances HIV replication and makes the virus more pathogenic.

HIV Genetic Composition Vpr (viral protein R) Plays a role in the regulation of viral and cellular gene expression and may be important in viral assembly and infection of macrophages, it may also induce apoptosis. Vpu (viral protein u) Influences release of HIV from the cell surface and contributes to CD4 degradation within the endoplasmic reticulum.

Life Cycle of HIV

HIV Infections and Pathogenesis During the early phase of HIV infection before seroconversion, the virus propagates mainly in peripheral blood mononuclear cells (PBMC). Primary infection may cause a temporary depletion of CD4 + PBMCs HIV infection usually elicits strong cell-mediated immune responses (CD8+ cytotoxic T cells) and humoral responses help to clear virus load but fail to eradicate HIV infection. During asymptomatic period, the virus is not completely latent but remains active in lymphoid tissue as proved by PCR technique. Monocytes are resistant to destruction by HIV, they may act as a reservoir for the virus, as well as, a vehicle which transmits HIV to distant parts of the body.

HIV Infections and Pathogenesis The primary targets of HIV are activated CD4+ T4 helper lymphocytes but the virus can also infect several other cell types including macrophages.  one of the main role of CD4+ cells is to send signals to other types of immune cells, including CD8 killer cells, which then destroy the infectious particle. It is the loss of T4 helper lymphocytes that leads to immunosuppression in the patient and the consequent fatal opportunistic infections.

Death The window period is time between potential exposure to HIV infection and the point when the test will give an accurate result. During the window period a person can be infected with HIV and be very infectious but still test HIV negative.  Viral eclipse: The period of time between infection by a virus and the appearance of the mature virus 

Epidemiology of HIV The world pandemic of AIDS has been with us for more than thirty years and about 39 million people have died of the disease. About 1.2 million people around the world die of AIDS each year. Today, at least 36.9 million people are infected and there are more than 7,000 new infections every day. In 2015, 15 million infected persons were receiving anti-retroviral therapy. In sub-Saharan Africa, more than 22 million people are living with HIV infection, accounting for about 70% of total cases.

36.9 million (100%)

Modes of Transmission Sexual contact (homosexual, heterosexual) Transplacental transmission Drug injection Percutaneous occupational exposure Receipt of infected blood Receipt of contaminated organs or tissues Breast feeding

Common Opportunistic Infections and Malignancies Associated with AIDS Bacteria Mycobacterium species Streptococcus pneumonia Haemophilus influenza Salmonella species Viruses Herpes simplex Herpes zoster Epstein-Barr virus Adenovirus Cytomegalovirus

Common Opportunistic Infections and Malignancies Associated with AIDS Fungi Candida albicans Histoplasma capsulatum Cryptococcus neoformans Protozoa Toxoplasma gondii Pneumocystis carnii Cryptosporidium species

Common Opportunistic Infections and Malignancies Associated with AIDS Kaposi’s sarcoma Burkitt-like lymphoma Hodgkin’s disease CNS lymphoma Immunoblastic sarcoma Peripheral organ lymphoma Lymphatic pre-leukemia

Prevention and Control Health education Early diagnosis Blood supply testing Early therapy Counseling services

Prevention of HIV Infection in Health Care Workers Wear coats and gloves when processing patient specimens Use masks and eyewear if splashing or aerosolization is anticipated Use precautions when handling needles and lancets Decontaminate work surfaces with a chemical germicide, e.g., chlorox Wash hands and remove protective clothing before leaving work place Dispose of contaminated materials in autoclavable bags Avoid contaminating the outside of containers upon specimen collection-the lid should be tight

Targets for Antiviral Therapy

Targets for Antiviral Therapy Resistant strains of HIV-1 to many drugs have emerged. A combination of antiviral drugs is recommended to overcome resistant strains Combined therapy may include “Highly Active Antiretroviral Therapy; HAART”, for example: one protease inhibitor plus two reverse transcriptase inhibitors Three reverse transcriptase inhibitors

Gene Therapy Take stem cells from the HIV patients' blood, then "knock out" a gene known as CCR5, which controls a protein that allows HIV to enter a cell.

Problems Facing the development of Effective vaccine against HIV: Antigenic diversity due to rapid mutation rate and recombination thus escaping from antiretroviral immune recognition Lack of a small animal model Live attenuated vaccine may revert to virulence Early establishment of latent viral reservoirs Viral evasion of humoral and cellular immune responses Little pharmaceutical interest

Diagnosis of HIV Infection Assays for the Diagnosis of HIV Infection Serological screening Antigen detection Cell culture Gene amplification “polymerase Chain Reaction, PCR” CD4 count

Diagnosis of HIV Infection Serological Screening Detects circulating anti-HIV antibodies ELISA … must be confirmed by: Immunofluorescence, Radioimmunoprecipitation, or Western blot [detects p24, gp41, gp120] Molecular Biology Techniques Reverse transcriptase-polymerase chain reaction(RT-PCR).