ACQUIRED IMMUNODEFICIENCY SYNDROME (AIDS) ▪Introduction ▪Epidemiology ▪Structure of HIV ▪Pathogenesis and life cycle of HIV ▪Clinical features AIDS ▪ Caused by Human Immunodeficiency Virus(HIV) - Retrovirus ▪ Characterized by profound immunosuppression that leads to opportunistic infections, secondary neoplasms and neurologic manifestations ▪ 3 major routes of transmission – Sexual contact – Parenteral inoculation – Passage of virus from infected mothers to their newborn High risk categories ▪ Sexual transmission – – – – Dominant mode of infection world wide Homosexual transmission Heterosexual transmission Enhanced by coexisting sexually transmitted diseases High risk categories ▪ Parenteral transmission – IV drug abusers – Recipients of blood transfusions ▪ Mother to infant transmission – In utero by transplacental – During delivery through infected birth canal – most common – After birth by ingestion of breast milk HIV Virus ▪ Lentivirus family ▪ Non transforming human retrovirus ▪ HIV – 1 and HIV-2 - genetically different but related forms ▪ HIV –1 – Most common type associated with AIDS in US,Europe and central africa ▪ HIV –2 – Principally in West Africa and India Structure of HIV ▪ Spherical ▪ Cone shaped core surrounded by lipid envelope ▪ Lipid envelope- derived from host cell membrane Structure of HIV ▪ Viral core contains – Major capsid protein p24 – Nucelocapsid protein p7/p9 – Two copies of viral genomic RNA ▪ Contains gag,pol and env genestypical of retroviruses – Three viral enzymes – Proteae – Reverse transcriptase – integrase Structure of HIV ▪ p24 – Most abundant viral antigen – Detected by ELISA ▪ Viral core is surrounded by matrix protein p17 ▪ 2 glycoproteins in viral envelope – gp 120 – gp41 Pathogenesis of hiv infection ▪ The HIV virion expresses a cell surface protein/antigen called gp120, that aids in the binding of the virus to the target cells. Once the virus enters the human body it attaches itself to the target cell via the CD4 receptors on the surface of the target cell and therefore gains entry into the target cell. Gp120 is responsible for tropism/attraction to CD4+ receptors. This function helps in entry of HIV into the host cell. ▪ In addition gp120 also binds to two coreceptors CXCR4 and CCR5 on the host cell surface. They too assist in the entry of HIV into the host cell. ▪ The T-lymphocytes have surface CD4 receptors (CD4+ T lymphocytes) to which HIV can attach to promote entry into the cell. Human immunodeficiency virus is shown crossing the mucosa of the genital tract to infect CD4+ T-lymphocytes. A Langerhans cell in the epithelium is shown in red in this diagram NOTE: The probability of infection depends on both the number of infective HIV virions in the body fluid which contacts the host as well as the number of cells with CD4 receptors available at the site of contact. Pathogenesis of hiv infection ▪ Retroviruses are unable to replicate outside of living host cells because they contain only RNA and do not contain DNA. Therefore once HIV infects a cell, it must use its reverse transcriptase enzyme to transcribe/ convert its RNA to host cell proviral DNA for replication. ▪ The enzyme, reverse transcriptase in the HIV helps in the reverse transcription (i.e. conversion) of RNA to proviral DNA. This HIV proviral DNA is then inserted into host cell genomic DNA by the integrase enzyme. ▪ Once the HIV proviral DNA is within the infected cell's genome the HIV provirus is replicated by the host cell to produce additional HIV virions which are released by surface budding. Alternatively the infected cells can undergo lysis with release of new HIV virions which can then infect additional cells. HIV viral particles are seen adjacent to the cell surface in this electron micrograph HIV life cycle Establishment of HIV Infection ▪ Macrophages and Langerhans cells are important both as reservoirs and vectors for the spread of HIV in the body including the CNS. Both macrophages and Langerhans cells can be HIV-infected but are not destroyed themselves. HIV can then be carried elsewhere in the body. ▪ Once the infection extends to the lymph nodes, the HIV virions are trapped in the processes of follicular dendritic cells (FDC's), where they provide a reservoir and infect CD4+ T lymphocytes that are passing through the lymph node. The FDC's themselves become infected, but are not destroyed. ▪ The target cells are: blood monocytes and tissue macrophages, T lymphocytes, B lymphocytes, natural killer (NK) lymphocytes, dendritic cells (i.e. the Langerhans cells of epithelia and follicular dendritic cells in lymph nodes), hematopoietic stem cells, endothelial cells, microglial cells in brain, and gastrointestinal epithelial cells. Establishment of HIV Infection ▪ In addition HIV has the ability to mutate easily. This high mutation rate leads to the emergence of HIV variants within the infected person's cells that are more toxic and can resist drug therapy. Over time, different tissues of the body may harbor differing HIV variants Natural history ▪ 3 phase – Acute retroviral syndrome – Chronic phase – Clinical AIDS • Primary(acute) infection • Virus dissemination • Development of host immune responses Acute Retroviral Syndrome PRIMARY INFECTION ▪ Virus enters through mucosal epithelium ▪ Infects memory CD4+ T cells in mucosal lymphoid tissue ▪ Death of many infected cells DISSEMINATION OF VIRUS ▪ DCs at sites of viral entry capture the virus and migrate into the lymphnodes ▪ Pass HIV to CD4+ T cells – cell to cell contact ▪ Viral replication in lymph nodes ▪ Viremia ▪ Infects helper T cells ,macrophages and DCs in peripheral lymphoid tissues DEVELOPMENT OF HOST IMMUNE RESPONSE ▪ Humoral and cell mediated immune responses ▪ Seroconvertion and development of virus specific CD8+ cytotoxic T cells(3 – 7 weeks) ▪ Partially control the infection ▪ A drop in viremia to low but detectable levels(12 weeks) Acute Retroviral Syndrome ▪ Clinical presentation of initial spread of the virus and host responses ▪ 40 – 90% of infected individuals ▪ Occurs 3-6 weeks after infection and resolves spontaneously in 2 -4 weeks ▪ Marked by nonspecific self limited acute illness with flu like symotoms – – – – – – Sorethroat Myalgia Fever Weight loss Fatigue Rash,cervical adenopathy,diarrheas,vomiting Chronic infection;Phase of clinical latency ▪ Lymph nodes and spleen – continues viral replication and cell destruction ▪ Few or no clinical manifestations- Clinical latency period ▪ Majority of peripheral blood T cell have no virus ▪ Destruction of CD4+ in lymphoid tissues and in blood continues – number steadily declines ▪ May develop minor opportunistic infections- candidiasis,herpes zoster,TB AIDS ▪ Breakdown of host defense,increase in viral load,severe life threatening clinical disease – – – – – Long lasting (>1 month) fever Fatigue Weight loss Diarrhea Generalised LN enlargement ▪ Severe opportunistic infections,secondary neoplasm,neurologic disease ▪ In the absence of treatment,most patients progress to AIDS after a chronic phase of 7-10 years ▪ Exceptions – Rapid proggressors- chronic phase 2-3 years after primary infection – Long term non progressors- Untreated infected individuals who remain asymoptomatic for 10 years or more, with stable CD4+ T cell count and low viral load – Elite controllers- 1% of infected individuals with have undetectable plasma virus Opportunitic Infections Protozoal and Helminthic Infections ▪ Cryptosporidium (enteritis) ▪ Pneumocystis (pneumonia or disseminated infection) ▪ Toxoplasma (pneumonia or CNS infection) Fungal Infections ▪ Candida (esophageal, tracheal, or pulmonary) ▪ Cryptococcus (CNS infection) ▪ Coccidioides (disseminated) ▪ Histoplasma (disseminated) Bacterial Infections Viral Infections ▪ Mycobacterium ▪ Cytomegalovirus (pulmonary, intestinal, retinitis, or CNS infections) – “atypical,” - Mycobacterium aviumintracellulare(disseminated or extrapulmonary) – Mycobacterium tuberculosis(pulmonary or extrapulmonary) ▪ Herpes simplex virus (localized or disseminated infection) ▪ Nocardia (pneumonia, meningitis, disseminated) ▪ Varicella-zoster virus (localized or disseminated infection) ▪ Salmonella infections, disseminated ▪ Progressive multifocal leukoencephalopathy Neoplasms Kaposi sarcoma Primary lymphoma of brain Invasive cancer of cervix Kaposi sarcoma most common neoplasm in patients with AIDS caused by HHVS - KS herpesvirus with Cofactor HIV proliferation of spindle cells with slitlike vascular spaces express markers of both endothelial cells and smoothmuscles Affects skin, G12, mucousmembrane CN and lungs. Lymphomas ▪ Commonly it is B-cell Non Hodgkins Lymphoma. ▪ They are typically of a high grade and often in the brain. ▪ They are very aggressive and respond poorly to therapy.
