PATHOGE

Rajani A. PrabhuMI-1414MSC-IIVirology ISA II

PATHOGENISIS OF AIDS

INTRODUCTIONHIV is a member of the lentivirus family, a subgroup of retroviruses, RNA viruses that replicate via a DNA intermediate.AIDS: acquired immunodeficiency syndromeAIDS is defined by a loss of CD4 T lymphocytes or the occurrence of opportunistic infections or cancers.

MORPHOLOGY

GENOME OF HIV

GENOME OF HIVThe genes of HIV in the virion(RNA) and integrated into host cell genome (DNA).There are two types of genes analyzed- a) Structural genes encode for products which participate in formation of functional structure of virus 1) gaggene encodes for core and shell of virus. The p24 antigen (major core antigen) can be detected in serum during the early stages of infection till the appearance of the antibodies.

GENOME OF HIV 2) polgene Encodes for the polymerase, reverse transcriptase and other viral enzymes such as protease and integrase.3) envgene determines the synthesis of envelop glycoprotein gp 160 which is cleaved into gp 120 and gp41. The antibodies to gp 120 are the first to appear after HIV infection and are present in circulation till the terminal stage of infection

b) Non structural and Regulatory genes 1) vif-(Viral infectivity factor gene) influences infectivity of viral particles. 2)vpr-stimulates promoter region of the virus3) vpu(in HIV-1 ) and vpx(in HIV-2)

PATHOGENESISInfection is transmitted when virus enters the blood or tissues of a person and comes in to contact with a suitable host cell, principally the CD4 lymphocytes. The virus may infect any cell bearing the CD4 antigen on the surface. Primarily these are the CD4 + helper T lymphocytes.

CELLS AFFECTEDLymphoreticular system: CD4+ T-Helper cells Macrophages MonocytesB-lymphocytes Certain endothelial cells Central nervous system: Microglia of the nervous system Astrocytes Oligodendrocytes Neurones

STEPS OF VIRAL ENTRY INTO HOST CELLATTACHMENT OF VIRUS INTO THE HOST CELLSpecific binding of the virus to the CD4 receptors is by the envelop glycoprotein gp120.VIRUS TO CELL FUSIONFor infection to take place the cell fusion is essential. This is brought about by the transmembrane glycoprotein gp 41. HIV-1 utilizes two major co-receptors along with CD4 to bind to, fuse with, and enter target cells; these co-receptors are CCR5 and CXCR4, which are also receptors for certain endogenous chemokines.

UNCOATING OF THE VIRAL ENVELOPE AND ENTRY OF NUCLEAR CAPSID CORE INTO THE CELLAfter fusion of virus with the host cell membrane, HIV genome is uncoated and internalized in to cell. Viral RNA is released into the core cytoplasm

VIRAL TRANSCRIPTIONviral reverse transcriptase mediates transcription of its RNA; RNA-DNA hybrid is formed. Original RNA strand is degraded by ribonuclease H, followed by synthesis of second strand of DNA to yield double strand HIV DNA

INTEGRATION INTO THE HOST DNA AS PROVIRUS The double stranded DNA is integrated in to the genome of the infected host cell through the action of the viral integrase enzyme, causing a latent infection.Fate of provirusFrom time to time, lytic infection is initiated releasing progeny virions, which infect other cells.The long and variable incubation period of HIV is because of the latency. In an infected individual the virus can be isolated from the blood, lymphocytes, cell free plasma, semen, cervical secretions, saliva, urine and breast milk.

STEPS OF VIRAL EXIT FROM HOST CELLTRANSCRIPTION BACK INTO RNAThe viral DNA is transcribed into RNA and multiple copies of viral RNA are produced.There are only nine genes in HIV RNA, and these code for the production of structural proteins, accessory proteins, and enzymes essential for the virus's replicative cycle.

VIRION ASSEMBLY- With the help of viral protease, the new virions are assembled into the polypeptide sequences needed for HIV virion formation and infectivity.CELL LYSIS- The infected cell is made to burst open, presumably by the action of cellular proteins.

Stages of AIDSHIV infection can generally be broken down into four distinct stages: primary infection, clinically asymptomatic stage, symptomatic HIV infection, and progression from HIV to AIDS.

Acute HIV infection Primary infection also can be said as acute stage of infection.This stage of infection lasts for a few weeks and is often accompanied by a short flu-like illness.The virus attacks and destroys the infection-fightingCD4 cellsof the immune system. HIV can be transmitted during any stage of infection, but the risk is greatest during acute HIV infection.

This phase is also calledwindow period or phase of Sero conversion.There is production of CD8+ cells which kills HIVInfected cells.Some patients do not develop symptoms after they first get infected with HIV.

Chronic HIV infectionThe second stage of HIV infection is chronic HIV infection (also called asymptomatic HIV infection or clinical latency.) During this stage of the disease, HIV continues to multiply in the body but at very low levels. People with chronic HIV infectionmay not have any HIV-related symptoms, but they can still spread HIV to others. The patients show positive antibody tests during this phase. Without treatment with HIV medicines, chronic HIV infection usually advances to AIDS in10 to 12 years.

Symptomatic infectionOver time the immune system becomes severely damaged by HIV. This is thought to happen for three main reasons:The lymph nodes and tissues become damaged or 'burnt out' because of the years of activity.HIV mutates and becomes more pathogenic, in other words stronger and more varied, leading to more T helper cell destruction.The body fails to keep up with replacing the T helper cells that are lost.

Symptomatic HIV infection is mainly caused by the emergence of certainopportunistic infectionsthat the immune system would normally prevent. This stage of HIV infection is often characterised by multi-system disease and infections can occur in almost all body systems

0PORTUNISTIC INFECTIONS IN AIDS

AIDSAs the immune system becomes more and more damaged the individual may develop increasingly severe opportunistic infections and cancers, leading eventually to an AIDS diagnosis.When the CD4 lymphocyte count drops below 200/microliter, then the stage of clinical AIDS has been reached.

Mechanism of CD4 T cell depletion in HIV infection

Cause of immunodeficiency

EFFECTSMonocyte, macrophage system is also affected apparently due to the lack of the activating factors by the T4 lymphocytes.The activity of NK cells and Tc (T Cytotoxic) cells are also affected. The clinical manifestations are due to failure of the immune responses. This renders the patient susceptible to life threatening opportunistic infections and malignancies.

The most prominent effect of HIV is its T-helper cell suppression and lysis leading to the familiar AIDS complications. Infection of the cells of the CNS cause acute aseptic meningitis, subacute encephalitis, vacuolar myelopathy and peripheral neuropathy. Later it leads to even AIDS dementia complex. The CD4-gp120 interaction is also permissive to other viruses like Cytomegalovirus, Hepatitis virus, Herpes simplex virus, etc. These viruses lead to further cell damage i. e. cytopathy.

Disease progression through different phases in HIV infected cases

referencesInterim WHO clinical staging of HIV/AIDS and HIV/AIDS case definitions for surveillance 2005.Pantaleo G (1993) New concepts in the immunopathogenesis of human immunodeficiency virus infection. N Engl J Med. 328(5):327-35.Piatak M., M.S Saag, L.C Yang, S.J Clark, J.C Kappes, K.C Luk, B.H Hahn, G.M Shaw and J.D Lifson (1993) High levels of HIV-1 in plasma during all stages of infection determined by competitive PCR. Science 259 (5102): 17491754.

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