5) Acquired immune deficiency syndrome (AIDS) 2021.ppt

Dr. Inas Almazari Zarqa University  Introduction Acquired immune deficiency syndrome (AIDS) was 1 st identified in 1981 in a small gp of gay men in San Francisco area who presented with unusual opportunistic infections. Today, just >1 million Americans are living wi...

Dr. Inas Almazari Zarqa University  Introduction Acquired immune deficiency syndrome (AIDS) was 1 st identified in 1981 in a small gp of gay men in San Francisco area who presented with unusual opportunistic infections. Today, just >1 million Americans are living with HIV infection. Annual rate of HIV infections ↓ ~18% between 2008- 2014. Highly effective antiretroviral therapy has greatly improved the quality of life and life expectancy for patients infected with HIV. It is estimated that 95% of people with HIV infection now live in developing countries. Globally only 46% of individuals infected with HIV are receiving antiretroviral therapy. 02  HIV structure and lifecycle The HIV virus is an RNA virus that belongs to retroviruses family For retroviruses to replicate they must utilize a special enzyme called reverse transcriptase, which allows the viral RNA genome to be first copied into a DNA/RNA hybrid and then into mRNA, which can be translated into new viral proteins by host cell DNA and RNA polymerase. The HIV genome also contains codes for two other important enzymes, HIV integrase, and HIV protease.  Structurally, HIV has an inner protein core containing a double strand of identical (+/+ RNA).  The inner protein core of HIV is surrounded by a second protein layer called the protein shell.  The protein shell in turn is encased in a lipid bilayer called the lipid envelope. This lipid bilayer is taken from host cell membranes when new HIV particles “bud” or exocytose from host cells. Protruding from the lipid envelope are numerous glycoprotein spikes or peplomers, which serve as organs of attachment to host cell membranes.  HIV peplomers comprise two distinct glycoproteins,  gp41: serves to anchor the peplomer in the HIV lipid envelope  gp120: serves as a specific binding site for the human cellular proteins called CD4 (CD stands for cluster of differentiation).  These CD4 proteins are found in greatest concentration on the surfaces of helper T-cells (CD4+ lymphocytes, or CD4 cells) and in lesser concentrations on monocytes and macrophages.  When HIV encounters a CD4-bearing cell, the glycoprotein gp120 part of the peplomer binds specifically to it at the CD4 site. This binding uncovers the gp41 glycoprotein on the HIV peplomer, which now embeds itself in the host cell membrane  HIV structure and lifecycle Effective HIV binding to CD4 cells requires that HIV also attach to a second set of receptors on the surface of CD4 cells called chemokine receptors. Once fusion of the HIV has occurred with the host cell, the viral core (containing the HIV genome) is injected into the host cell. Inside the host cell, the viral core breaks down and the HIV genome is released into the host cell cytoplasm. This step is called uncoating. The free HIV RNA is copied into a DNA/RNA hybrid molecule with the assistance of HIV reverse transcriptase. The single strand of viral DNA is then released from the DNA/RNA hybrid and copied into a double strand of viral DNA by cellular polymerases. The double strand of HIV DNA becomes integrated into the host cell DNA through the actions of the HIV integrase enzyme.  HIV structure and lifecycle Then, each time the cellular DNA is expressed, viral DNA is also expressed. New HIV viruses are formed as the viral proteins are translated by the host cell from mRNA. These newly replicated viruses can leave the host cell by budding or exocytosis. The newly formed HIV viruses, however, are not fully “mature” or functional until they are enzymatically modified by HIV protease enzymes to the fully active and infectious state. A number of genetically different yet related HIV viruses have been identified. Some appear to be particularly virulent because the progression of disease is quite rapid, others are more “benign” because disease progression occurs more slowly.  CHEMOKINE MUTATION AND RESISTANCE TO HIV INFECTION It has long been observed that certain untreated individuals infected with HIV may progress very slowly in the course of their disease if at all. These “slow progressors” or “nonprogressors” may have a natural mutation in the chemokine proteins (CCR5) on the surface of their CD4 cells that are used by HIV for attachment. This mutation prevents HIV from fully attaching to their CD4 cells and makes viral entry more difficult. This finding led to development of the HIV drug maraviroc, which impairs HIV entry into CD4 cells by blocking CCR5 chemokine proteins on the surface of CD4 cells. HIV life cycle  Stages in an HIV infection 1. Acute illness stage 2. Asymptomatic stage 3. Symptomatic or AIDS stage  1. Acute illness stage  Generally occurs several weeks after infection with the virus.  Manifestations include acute-onset fever, headache, malaise, lymphadenopathy, sore throat and skin rash.  Symptoms subside within several weeks  asymptomatic.  During the acute illness phase, there is a transient reduction in circulating CD4+ and CD8+ lymphocytes.  2. Asymptomatic stage  Following the acute illness stage, most patients go into asymptomatic period that may be highly variable in duration. Patients generally remain in relatively good health for a period of 5–10 years. During this period there is slow but persistent destruction of immune cells, particularly CD4 cells. Toward the end of this period, circulating levels of CD4 cells significantly from a normal range of approximately 500–1,500 cells/μL to less than 500 cells/μL. Levels of CD8 cells may also show moderate decreases.  3. Symptomatic or AIDS stage  When circulating levels of CD4 cells fall below a critical level (generally 200 cells/μL), the infected individual becomes symptomatic (AIDS-related complex (ARC))  Symptoms include fever, night sweats, diarrhea and opportunistic infections  “Opportunistic” organisms are those that take advantage of the patient’s weakened immune status to infect their system  unique to AIDS or immune- compromised patients.  3. Symptomatic or AIDS stage  As levels of CD4 cells continue to fall, levels of HIV in the blood can increase markedly  Malignant cancers may also appear  The most common is Kaposi’s sarcoma, a malignant neoplasm that can occur in skin, lymph nodes and viscera.  Neurologic manifestations are common in the late stages of HIV infection and can include AIDS dementia complex in which the patient suffers loss of memory, personality changes and loss of control over motor functions. The AIDS stage is also associated with the development of wasting syndrome, or cachexia, characterized by marked weight loss, anorexia, metabolic changes and endocrine dysfunction.  Epidemiology of HIV infection  HIV virus is a blood-borne pathogen → transmitted via contact with contaminated body fluids e.g. blood & blood factor transfusions, sharing of contaminated needles, unprotected sexual intercourse (vaginal or anal), from infected mothers to their fetuses.  HIV virus appears in breast milk → breast-feeding is not recommended  HIV virus may also be detected in trace amounts in the saliva of infected individuals; however, there is no current evidence that the virus can be transmitted by casual contact.  Laboratory diagnosis of HIV Enzyme immunoassay (EIA) is used to detect HIV antibodies. A positive EIA must be confirmed by Western blot or immunofluorescence assay (IFA) to detect specific HIV proteins. HIV core protein p24 is the most abundant. Other HIV proteins e.g. p55, p40, gp120 & gp41 may also be part of the analysis. Polymerase chain reaction (PCR) is a technique used to measure HIV DNA levels (viral load).  Rationale for treatment of HIV  Prevent viral replication in infected cells by inhibiting various steps in the HIV life cycle.  Treatment should begin immediately upon diagnosis for all patients and regardless of their CD4 cell counts..  Treat opportunistic infections when they arise and prophylactically.  Provide nutritional, medical and emotional support for patients with a chronic illness.  Treatment of HIV  The most effective way is through proper prevention  Considerable research is currently being conducted on developing an HIV vaccine that would protect individuals from HIV infections even after exposure to the virus.  Treatment of HIV The effectiveness antiretroviral therapy is determined be measuring CD4 counts and plasma HIV RNA (viral load). Currently available drugs for the treatment of HIV target various phases of the HIV life cycle These agents are always used in combination to enhance effectiveness and reduce the possibility of drug resistance. The current HAART or highly active antiretroviral therapy regimen involves the use of three different antiretroviral drugs from at least two different drug classes. Considerable research is currently being conducted on developing an HIV vaccine that would protect individuals from HIV infections even after exposure to the virus.  HIV drug resistance  The low fidelity of reverse transcriptase coupled with high rates of HIV replication and genetic recombination  numerous resistant HIV variants  HIV drug resistance may be partially offset by using several antiretroviral drugs in combination with one another  These HIV drug “cocktails” are highly effective in reducing detectable levels of HIV and offset the problem of resistance  Genotypic and phenotypic testing of HIV viruses for specific drug resistance helps clinicians in choosing the best drug to treat a particular strain of HIV  HIV drug resistance testing  Genotypic resistance testing: More than 100 drug-resistant HIV mutants have thus far been identified along with many of the specific genetic mutations that confer the resistance. Genotypic testing looks for one or more of specific resistant mutations in a particular HIV. Testing is generally rapid and relatively simple but can only detect a single or few mutations in any one virus and may not detect new mutations that have arisen.  HIV drug resistance testing  Phenotypic resistance testing:  Directly measures the ability of a particular HIV to grow in the presence of a specific drug or drugs  Can be a direct measure of drug susceptibility for a specific virus.  Expensive and technically more difficult and time- consuming than genotypic testing. THANKS