HIV/ AIDS

Sexually Transmitted disease

Acquired Immunodeficiency Syndrome (AIDS)

Disease of the human immune system caused by the HIV Infection by HIV progressively reduces the effectiveness of the immune system and leaves individuals susceptible to opportunistic infections and tumors. AIDS is a condition that appears as the last stage in HIV infection HIV person is diagnosed as having AIDS, if he/ she has:

any AIDS defining condition, or CD4 count less than 200 cells/ mm3

Some AIDS defining conditions:

Candidiasis Cytomegaloviral disease Kaposis sarcoma Mycobacterium avium complex Pneumocystis jiroveci Pneumonia Recurrent pneumonia Pulmonary Tuberculosis invasive Cervical Cancer Wasting syndrome etc

Causative agent: HIV

HIV: Human Immunodeficiency Virus

Classification: Genus: Lentivirus Family: Retroviridae (Retrovirus)

Picture: Scanning electron micrograph of HIV-1 budding (in green) from cultured lymphocyte. This image has been colored to highlight important features; from the original black and white view of this image. Multiple round bumps on cell surface represent sites of assembly and budding of virions.

Scanning electron micrograph of HIV-1 budding from cultured lymphocyte

Multiple round bumps on cell surface represent sites of assembly and budding of virions.

Morphology: HIV

Shape:

Spherical enveloped virus about 90- 120 nm in size Outer envelop of lipoprotein (lipid & viral protein), with spikes on the surface

Envelop:

Core:

Central helical core of viral capsid proteins surround the genome HIV virion core looks like a truncated cone
consists of 2 identical copies of single stranded viral RNA in association with viral RNA is the reverse transcriptase (DNA dependent RNA polymerase) enzyme Integrase enzyme and two cellular tRNAs are also present Contains various genes & long terminal repeats

Genome:

2 strains of HIV

HIV-1

The original isolates of HIV & the related strains prevalent all over the world belong to HIV type-1

HIV-2

HIV strains first isolated from West Africa in 1986, which react with HIV type 1 antiserum very weakly or not at all have been termed as HIV-2 Less virulent rarely causes full blown AIDS probably does not spread as widely & as rapidly as HIV-1

Viral genes & antigens

HIV genome contains : Genes/ LTR GENES: Structural genes:

Gag gene codes for group specific antigen proteins (p) that constitute the nucleocapsid shell; p 55 p17, p7, p9 & p24 (constitute core & shell) Env genes encodes the envelop glycoprotein (gp); gp 160 gp 120 (surface spike) , gp 41 (transmembrane pedicle protein) Pol genes codes for reverse transcriptase, endonuclease & integrase/ ligase {p100 p31, p51 and p64}

Regulatory genes

tat (transactivator of transcription) gene (p16) rev (regulator of expression of viral proteins) gene nef (negative expression factor) gene (p19) vif (virion infectivity factor) gene vpr gene represents the stimulating promotor region of the virus vpu (in HIV-1) & vpx (in HIV-2): codes for small viral proteins which enhance maturation and release of progeny virus from cells. Identification helps to distinguish HIV- 1 from HIV- 2

Long Terminal Repeat (LTR)

LTR sequence present at each end of the genome LTR contains promoters, enhancers & other gene sequence used for binding different cellular factors LTR in provirus is linked to the host DNA & exerts regulatory control on the provirus gene function

Structural proteins

Glycoprotein gp 160

Consists of a transmembrane segment gp41 bound non- covalently to gp 120, a major external glycoprotein

gp 120 contains conserved highly variable region that binds to CD4 protein of host cell and is highly immunogenic gp41 is thought to have fusion inducing function The penetration of the host cell by HIV involves attachment of gp120 to CD4 protein (receptor for the virus) & fusion is mediated by gp 41 gp41 may also mediate penetration in some cells lacking CD4 molecules

Inner core capsid protein (p24) forms the capsid Matrix protein (p 17) forms layer between the core & envelop of the virus Nucleic acid binding proteins (p6, p7)

Life cycle of HIV

HIV: modes of transmission

HIV transmission occurs via body fluids (through blood, semen, vaginal fluid & via mother to child) Known routes: Inoculation in blood

Transfusion of blood & blood products Sharing needles by intravenous drug abusers Needle stick injury, open wound, & mucous membrane exposure in health care workers Tattoo needles

Sexual contact Transplacental or perinatal transmission

Transplacental transmission Peripartum transmission Breast milk

Pathogenesis (I)
The natural evolution of HIV infection can be considered in the following stages: Acute HIV infection

Within 3-6 wks of infection with HIV, about 50% of persons experience low grade fever, malaise, headache, lymphadenopathy etc : Seroconversion illness Spontaneous resolution occurs within weeks In some seroconversion occurs without any apparent illness

Asymptomatic or latent infection

All persons infected with HIV, whether or not they experience seroconversion illness, pass through a phase of symptomless infection (clinical latency) which may last upto several years They show positive HIV antibody during this phase & are infectious Clinical latency does not mean microbiological latency as virus multiplication goes on throughout The host mounts an immune response against the virus, which can only limit the virus load, but not clearly complete it A chronic persistent infection with varying degrees of viral multiplication is the result There is a steady decrease in the CD4+ T cell

Pathogenesis (II)

Persistent generalized lymphadenopathy (PGL)

Defined as presence of enlarged lymph nodes, at least 1 cm, in diameter, in two or more non-contiguous sites, that persists for at least 3 months, in the absence of any current illness or medication that may cause lymphadenopathy The condition is itself benign but may progress to ARC or AIDS

AIDS related complex (ARC)

Sufferers become considerably immunodeficient and suffers from various constitutional symptoms or minor opportunistic infections Typical constitutional symptoms are: fatigue, unexplained fever, persistent diarrhea, marked weight loss (>10%) etc Common OI: oral candidiasis, herpes zooster, hairy cell leucoplakia, salmonellosis or TB. Generalized lymphadenopathy and splenomegaly are usually present Patients are usually severely ill progresses to AIDS

Pathogenesis (III)

AIDS

End stage; irreversible breakdown of immune defense mechanism leaves the patient prey to progressive OI & malignancies In early AIDS, many patients are ill only during episodes of infection which may respond to treatment AIDS defining conditions become progressive GI, CNS, Cutaneous, Malignant problems are frequent

Dementia

HIV may cause direct cytopathogenic damage in the CNS It can cross BBB leading to loss of higher functions, progressing to dementia

This diagram illustrates the relationship between HIV-1 virus load (red line) and CD4+ T-cell count (bue line) over time in a typical case of untreated HIV-1 infection.

Diagnosis (I)

Immunodeficiency can be established by:

Total leucocyte & lymphocyte count demonstrating leucopenia & a lymphocyte count usually below 2000/ mm3 Absolute CD4+ T cell (less than 200/ mm3) Reversed T4: T8 cell ratio Platelet count thrombocytopenia Raised IgG & IgA level Diminished CMI as indicated by skin tests Lymph node biopsy showing profound abnormalities

Diagnosis (II)
Specific tests for HIV infection Antigen detection

The major core antigen p24 is the earliest virus marker to appear in blood IgM antibodies, followed by IgG antibodies p24 capture assay (ELISA) : in the first few weeks after infection and in the terminal phase, the test is uniformly positive

Virus isolation (from peripheral lymphocytes) Polymerase Chain Reaction: DNA PCR & RNA PCR most sensitive and most specific test

Diagnosis (III)

Antibody detection

Demonstration of antibodies is the simplest and most widely employed technique for HIV diagnosis Window period seronegative infective stage it may take 2- 8 weeks for antibodies to appear Antibody screening not totally reliable for spotting infectious persons Antibodies tests will have to be done after 2-6 months to ascertain infection after a single sexual exposure Serological tests for anti- HIV antibodies are:

ELISA test Western Blot technique

Prevention
Safe sex Contaminated needles, syringes or other skin piercing equipments should not be shared with others All blood & blood products should be screened. Also applies to donation of semen, cornea, bone marrow, kidney & other organs Control of infection: Identification of HIV individuals amongst high risk groups Regular follow up of carriers

Immunoprophylaxis Although vaccines have been developed and used: no effective vaccine has yet been found out

Post exposure prophylaxis: Soon after exposure to HIV, drugs are used to prevent HIV infection 2 or 3 anti retroviral drugs taken several times of the day: usually a 4 weeks program Benefits of PEP in non- occupational exposure has not been established

Therapy

Antiretroviral therapy (ART)

Anti Retroviral (ARV) drugs inhibits the replication of HIV (by different mechanisms) Not a curative therapy cannot destroy the virus only controls the virus replication/growth

Antiretroviral Drugs fall under the following categories:

Nucleoside Reverse Transcriptase Inhibitor (NRTI) : Zidovudine, Didanosine, Stavudine, Lamivudine, Abacavir etc Non Nucleoside Reverse Transcriptase Inhibitor (NNRTI): Nevirapine, Efavirenz etc HIV Protease Inhibitors (HIV PIs): Indinavir, Lopinair, Ritonavir, Saquinavir etc Nucleotide Reverse Transcriptase inhibitors: Tenofovir HIV fusion inhibitors : Enfuvirtide (T- 20)

HAART

Initially 1 or 2 ARV drugs were used, but later proven ineffective HAART (Highly Active Anti Retroviral Therapy)

Introduced by WHO in 1996 Potent ARV regimens that includes a minimum of 3 drugs is referred to as HAART Such multi- drug regimens are found to have the potential for additive and synergistic effects against HIV & possible prevention or delay in the emergence of resistant strains Some common combinations include:

Stavudine/ Lamivudine/ Nevirapine Zidovudine / Lamivudine/ Nevirapine Stavudine/ Lamivudine/ Efavirenz Zidovudine/ Lamivudine/ Efavirenz etc