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HIV Disease and Complications of Immunodeficiency Chapter 29 HIV Disease Symptoms Appear after incubation period of 6 days to 6 weeks Usually consist of fever, headache, sore throat, muscle aches, enlarged lymph nodes and generalized rash Some develop CNS symptoms Range from moodiness and to seizures and paralysis Symptoms constitute acute retroviral syndrome (ARS) Typically subside in 6 weeks Acute illness followed by asymptomatic period Period may end with persistent enlargement of lymph nodes Lymphadenopathy syndrome (LAS) Immunodeficiency symptoms include fever, weight loss, fatigue and diarrhea Referred to as AIDS-related complex (ARC) HIV Disease Causative agent In U.S and most other parts of the world disease caused by human immunodeficiency virus type 1 (HIV-1) Belongs to lentivirus subgroup of retrovirus family HIV-2 is similar in structure to HIV-1 but is antigenically distinct Prominent cause of AIDS in parts of West Africa and India Has appeared in the U.S. Transmission is less efficient than HIV-1 Disease progresses slower HIV Disease Pathogenesis HIV Disease HIV attacks a variety of cell types Most critical are helper T cells Viral gp120 attaches to CD4 cell surface receptor Viral gp41 induces membrane fusion by interacting with chemokine cell surface receptor (CCR) After entry, DNA copies of RNA genome produced using reverse transcriptase viral enzyme DNA copy integrates and hides on host chromosome In activated cells virus leaves cell genome and kills cell Releases additional viruses to infect other cells Macrophages have CD4 receptors Infected macrophages are not killed but are impaired Eventually immune system becomes too impaired to HIV Disease Pathogenesis HIV Disease Destruction of immune system helper T cells by HIV can occur via multiple mechanisms Lysis following HIV replication Attack by HIV-specific cytotoxic CD8+ T lymphocytes CTL kill HIV-infected T cells Antibody-dependent cellular cytotoxicity Antibodies bind to gp120 and gp41 viral glycoproteins on infected T cells, facilitating the killing of those cells Autoimmune process Fusion of infected and uninfected cells Facilitated by gp120 and gp41 on infected cells and CD4 and CCR on uninfected cells Apoptosis HIV Disease Pathogenesis In nearly 80% of all cases immune system slowly loses ground to virus Peripheral CD4+ count steadily falls to nearly 50 cell /µl Symptoms usually appear when count falls below 200 cells/µl Atypical progression of disease occurs in roughly 10% of infected individuals Disease progresses rapidly to AIDS within a few months Another 5% - 10% do not experience a fall in CD4+ cells Maintain high levels of antibodies and CD8+ cells Disease progresses slowly May be AIDS-free for 20 years Epidemiology HIV Disease Indiscriminate sexual intercourse major factor in spread Promiscuous homosexual men most common Survey indicates before arrival of AIDS 33% to 40% of homosexual men had more than 500 lifetime partners Next most important mode of transmission is through blood and blood products By 1984 over 50% of hemophiliacs in U.S. were infected 10% - 20% of their sexual partners were HIV positive Today, blood transmission is usually I.V. drug use (needle-sharing) Third most important mode of transmission is mother to infant One in 10 pregnant HIV-positive women will miscarry Of live-born infants, 15% - 40% will develop AIDS Breast feeding carries significant risk of mother-infant transmission HIV Disease Prevention and Treatment No approved vaccine Most people infected are unaware Virus on surfaces can be inactivated with commercially available disinfectants and heat at 56°C for more that 30 minutes Knowledge of transmission greatest tool for control Use of condoms not 100% effective but have been shown to decrease transmission Avoidance of practices that favor HIV transmission HIV Disease Prevention and Treatment Treatment directed at “cocktails” of drugs Combination of reverse transcriptase inhibitors and protease inhibitors HAART = highly active antiretroviral therapy Reverse transcriptase inhibitors fall into two categories Nucleoside reverse transcriptase inhibitors Zidovudine (AZT), stavudine (D4T) and lamivudine (3TC) Non-nucleoside reverse transcriptase inhibitors Nevirapine, efavirenz and delavirdine HIV Disease Prevention and Treatment Highly-Active Anti-Retroviral Therapy Protease inhibitors 6 in use Act late in HIV replication to prevent packaging of viral proteins HAART does not cure AIDS Viremia becomes undetectable in approximately 50% of cases Will reappear in absence of treatment Many strains fail to respond to HAART due to resistance HIV Disease HIV vaccine prospects Currently no approved vaccines In theory, vaccine could be used in two ways Prevention vaccine Immunize uninfected individuals against disease Therapeutic vaccine Boost immunity of those already infected Successful vaccine must produce both mucosal and blood stream immunity get around HIV variability and stimulate cellular and humoral immunity HIV Disease HIV vaccine prospects Attenuated agent must not: Be capable of turning into disease-causing strain Be oncogenic Stimulate an autoimmune response Cause production of “enhancing” antibodies that could aid in the passage of HIV into the body’s cells Finally, vaccine should induce neutralizing antibodies against free virions and prevent direct spread of HIV from cell to cell Vaccine trial in humans has been undertaken for at least 10 experimental vaccines All have failed and prospects do not look favorable Kaposi’s Sarcoma Unusual tumor arising from blood or lymphatic vessels in multiple locations Common in men of Mediterranean and Eastern European descent Not as a sign of immunodeficiency Tumor began to appear in young men with HIV 2000 time higher than period before HIV So common among AIDS patients became AIDS-defining condition Kaposi’s Sarcoma Human herpesvirus-8 (HHV-8) detected in sarcomas Virus infects endothelial cells that line blood and lymphatic vessels Persists mostly in latent form Presence of virus associate with two dramatic changes that result in tumor formation: Cells assume spindle shape and proliferate Extensive formation of new blood vessels occurs B-Lymphocytic Tumors of the Brain B-cell lymphomas 60 to 100 times more common in AIDS patients compared to general public Intense, sustained replication of lymphoid cells is constant feature of HIV Lymph node enlargement reflects proliferation of lymphoid cells in response to high level unregulated cytokine release Replication of T cells occurs to replace those destroyed by HIV Epstein-Barr virus plays roll in B-cell lymphomas associated with AIDS Lymphomas rarely occur in brain except with AIDS patients Pneumocystosis Symptoms Typically begins slowly with gradually increasing shortness of breath and rapid breathing Fever is usually slight or absent 50% of patients have non-productive cough Skin and mucous membranes becomes dusky Due to poor oxygenation of blood Causative agentPneumocystosis - Pneumocystis carinii Tiny fungus belonging to phylum Ascomycota Formerly considered a protozoan Differs from many fungi in cell wall components Consequently resistant to many fungal medications Pathogenesis Spores of organism are inhaled into lung Attach to alveolar walls Alveoli fill with fluid, mononuclear cells and organisms Alveolar walls become thickened and scarred Pneumocystosis Epidemiology Widespread among animals including dogs, cats, horses and rodents Serological testing indicates almost all children are infected by age two and a half Infection is asymptomatic and generally eliminated in a year Source of transmission in humans is unknown Most cases of pneumocystosis occur in immunocompromised Epidemics among hospitalized malnourished infants and elderly nursing home residents suggest airborne spread Pneumocystosis Prevention and Treatment Disease used to occur in four-fifths of AIDS patients Was leading cause of death Disease largely preventable with regular doses of trimethoprim-sulfamethoxazole (TxS) Among the best medication for treating disease along with oxygen support Reduced mortality rate from nearly 100% to 30% After treatment patient must receive preventive medication indefinitely until rise in CD4+ T cells above 200 cells/μl Other Common Opportunistic Infections of AIDS Toxoplasmosis (Toxoplasma gondii) Herpesviruses Herpes simplex viruses 1&2 Cytomegalovirus Mycobacterium avis (TB-like disease)