HIV & Retroviruses_ Microbiology, Pathogenesis, Opportunistic Infections, & Antiretrovirals_ TBL.pdf

Overview For the last 45 years, HIV/AIDS has been a major epidemic affecting people across the world and responsible for the death of millions; to this day, HIV is still responsible for hundreds of thousands of deaths, especially in developing countries where access to antiretroviral therapy remains...

Overview For the last 45 years, HIV/AIDS has been a major epidemic affecting people across the world and responsible for the death of millions; to this day, HIV is still responsible for hundreds of thousands of deaths, especially in developing countries where access to antiretroviral therapy remains a challenge. In this activity, we will cover the biology and clinical features of retroviruses causing human disease (HIV-1, HIV-1, & HTLV-1), as well as the treatments for these infections. Learning Objectives By the end of this session, you will be able to meet the following learning objectives: HIV & Retroviruses: Microbiology, Pathogenesis, Opportunistic Infections 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. Describe, in detail, the characteristics and structure of retroviruses. List the retroviruses associated with human disease. Describe, in detail, the replicative cycle, as well as the molecules (host-derived and virusderived), involved in the replicative cycle of HIV and HTLV-1, Describe, in detail, the epidemiology of HIV and HTLV-1 (populations affected by these infections, infection distributions, transmission of infection, risk factors associated with each infection, etc.). List and describe the phenotypes, in context, of the cells infected by HIV and HTLV-1, as well as describe the consequences thereof. Describe the clinical features and pathophysiology of HIV and HTLV-1 infections, including correlations between CD4 counts, viral load, complications, opportunistic diseases, and causes of mortality associated with these viruses. Describe the immune responses to these infections and how these viruses circumvent host defense mechanisms. List and describe the laboratory diagnostic methods used for HIV and HTLV-1 infections; draw appropriate conclusions from test results. List the antiviral classes used in the treatment of HIV infections, and describe their mechanisms of action; describe the treatment of HTLV-1. Describe HIV antiviral resistance mechanisms. Describe the prevention of HIV and HTLV-1 infections. HIV & Antiretrovirals 1. 2. 3. 4. 5. 6. 7. Assign the antiretroviral drugs to their drug classes Describe the mechanism of action of the antiretroviral drugs Describe the mechanisms that provide resistance to antiretroviral drugs List the viral spectrum of the antiretroviral drugs Know the significant adverse effects of the antiretroviral drugs Know the significant pharmacokinetic properties of the antiretroviral drugs Identify an appropriate treatment regimen based on knowledge of the antiretroviral drugs. Relevant USMLE Content: Immune System Relevant USMLE Content: Blood & Lymphoreticular System Pathophysiology of HIV Infection And Causes Of T Lymphocyte Count Drops Primary Infection During the initial stage of HIV infection (i.e., acute stage, syn. mononucleosis-like syndrome, primary infection), viremia peaks and then drops when the CD8+ CTL response is initiated (HIV-specific CTLs & TH1 response). This response takes a couple of weeks to a month to arise. During this phase, the observed depletion of CD4+ T-lymphocytes in peripheral blood (CD4+ cell count) is not only due to the cytopathic effects of viral infection (direct viral cytopathic effects) but also to the destruction of infected CD4+ cells by CD8+ cytotoxic T-lymphocytes (this is the main cause of CD4 depletion during this stage of the infection), as well as sequestration of high numbers of both CD4+ and CD8+ cells in lymphoid tissues (which explains the lymphadenopathy associated with HIV primo-infection) and HIV-induced bone marrow suppression. After another few weeks, an efficient neutralizing antibody response develops. Consequently, the viral load decreases and the CD4+ counts increase again, but never back to their initial levels. This phase induces a febrile illness (mononucleosis-like syndrome) that lasts 3 to 4 months and is characterized by fever, malaise, pharyngitis, lymphadenopathy, headache, arthralgias, diarrhea, maculopapular rash, and/or meningoencephalitis. However, due to poor reverse transcriptase proofreading activity, escape mutants to CTLs and neutralizing antibodies rapidly arise, and the infection slides into the chronic (asymptomatic) phase. Chronic Stage Although this phase, which can last years, is asymptomatic, it is characterized by a steady-state level of HIV replication as well as a slow and steady decline in circulating CD4+ cells, potentially driven by viral reservoirs such as memory lymphocytes, macrophages, and gut cells. AIDS (End-Stage) The end-stage phase (full-blown AIDS) lasts months to years and is characterized by the appearance of severe, signature (AIDS-defining) opportunistic diseases such as Pneumocystis jirovecii, Cryptococcus neoformans, Mycobacterium avium, Toxoplasma gondii, or Cystoisospora belli infections among others, reactivation of herpesviruses such as VZV, EBV and HCMV, as well as HIVassociated dementia and malignancies such as Kaposi sarcoma, before death ultimately occurs as a result of opportunistic infections. The characteristic immunosuppression associated with AIDS is mostly due to impairments of HIVspecific and non-specific CD4+ cells and general impairment of CD8+ cells rather than to direct viral cytopathic effects. Eliminating circulating CD4+ T-lymphocytes results from heightened destruction (hyperimmune activation leading to apoptosis and pyroptosis, i.e., depletion by activation or T cell exhaustion) and diminished cellular production (bone marrow suppression by HIV & cytokines). Some patients can be characterized as slow, normal, or rapid progressors depending on their genetic background and initial viral set-point. Slow progressors are patients that possess a low viral load (60,000 copies/mL of serum) one year post-infection. The norm is approximately 30,000 copies per mL of serum. Some individuals with particular HLA-B alleles are more susceptible to HIV infection than others; likewise, some individuals with certain HLA-B alleles are more resistant. Furthermore, some individuals carrying mutations in the CCR5 co-receptor molecule are highly resistant to HIV infection. One such mutation is the delta-32 (Δ-32) deletion prevalent in some populations of northern European descent. This mutation leads to a non-functional CCR5 molecule that never reaches the cell membrane. Consequently, because the primo-infection is mediated by M-tropic viral particles, these individuals are, for the most part resistant to HIV infection. Other conditions also confer a significant amount of resistance to the development of AIDS: a nonsense mutation (428G→A) in the FUT2 gene (fucosyltransferase non-secretors) is associated with slow disease progression of HIV-1, as are certain combinations of NK cell Killer Immunoglobulin-like Receptor (KIR)/HLA-B expression [KIR3DL1 and KIR3DS1 + Bw4 motif (B*2705 and B*5701/B*5703)], individuals expressing high levels of APOBEC3G (apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like 3G or A3G), and individuals expressing broadly neutralizing antibodies early on during the infection. Some of these are referred to as long-term non-progressors or elite controllers. T cell exhaustion – the main mechanism that accounts for T cell drops in the pathophysiology of AIDS… As you recall, T lymphocyte activation leads to the T cell expression (CD4 & CD8) of immune checkpoint inhibitors [(PD-1, PD-2, CTLA-4, but also many others such as LAG3 (lymphocyte activation gene protein), TIM3 (T-cell immunoglobulin domain and mucin domain-containing protein 3), T-cell immunoreceptor with Ig and ITIM domains (TIGIT), 2B4 (CD244), & CD160] which lead to loss of T lymphocyte functions. With chronic antigen stimulation, as is the case for HIV infection, there is a loss in T cell IL-2, IFN-γ, and TNF-α secretion, as well as IL-7 and IL-15 secretion necessary for the maintenance of memory T lymphocytes, which are consequent to immune checkpoint stimulation; in addition, there is a loss of CD4 T lymphocyte help functions. In time, these exhausted cells will die from apoptosis and the CD4 and CD8 lymphocyte counts will drop, leading to high susceptibility to opportunistic infections. T cell exhaustion is responsible for most CD4 and CD8 deaths (& consequent lymphocyte count drops), and most of these are not HIV-infected. HIV Tropism HIV Tropism and Susceptible Leukocytes Virologic Response Definitions Pathophysiology of HTLV-1 ATL/ATLL HTLV-1 viral multiplication primarily relies upon T-lymphocyte replication, i.e. HTLV-1 chiefly replicates as a provirus during T-lymphocyte cell division. Viral fitness therefore depends on the capacity of the virus to induce cell cycling, which is mainly mediated by the viral protein Tax. HTLV-1 Tax protein, by analogy with the HIV Tat protein (discussed in the HIV section), is a transactivator that interacts with the cellular transcription factors that bind the proviral LTR (viral promoter/ enhancer region) to increase viral mRNA expression. However, in addition to its transactivating function, Tax also increases the expression of host proteins involved in the growth and survival of Tlymphocytes [e.g. IL-2/IL-2R, IL-15/IL-15R, Egr-1 and Egr-2 (early growth response genes-1 and -2)] mainly through the activation of the NF-κB (nuclear factor-kappa B), cAMP response elementbinding protein (CREB) and AP-1 (activator protein-1) transcription factors, while at the same time interfering with cell cycle regulators (e.g., the cell cycle inhibitor p16INK4A), DNA repair (downregulation of host DNA repair machinery proofreading) and apoptosis (e.g., p53). The pleiotropic effects of the Tax protein on viral and cellular genes, especially in conjunction with its expression level, therefore, play a central role in the pathogenesis of ATL. Progression to ATL is a multifactorial, multistep process. Specifically, early during the infection, the HTLV-1 genome integrates as a provirus into the host T-lymphocyte DNA, giving rise to HTLV-1 carrier resting cells. Antigen and IL-2 stimulation (such as during an infection, for example) of the infected carrier cells leads to the clonal expansion of these lymphocytes with concomitant proviral transcription of Tax, thereby exacerbating cellular expansion (see previous paragraph). Hence, this is essentially how the virus replicates. During that period, Tax is the major viral protein being produced, as well as the immunodominant one. Meanwhile, the expanding T-cell population is kept in check by an efficient CD8+ cytotoxic Tlymphocyte (CTL) response directed against Tax. This partly explains why leukemia does not develop at this stage and the infected individuals are asymptomatic. The immune pressure exerted by the CTL response, however, favors the selection of lymphocytes that eventually escape the immune response (escape mutants). Escape mutants arise mostly through genetic and epigenetic proviral DNA alterations, as well as through the action of viral proteins that hinder major histocompatibility class I (MHC-I)-restricted antigen presentation. Loss of Tax expression by 5’-LTR excision (the viral promoter/enhancer region of most HTLV-1 proviral genes) and missense or nonsense mutations in the Tax gene are examples of genetic alterations of proviral DNA. Tax-induced 5’-LTR DNA hypermethylation and histone modification are examples of epigenetic alterations of proviral DNA. Tax transcription is also suppressed by another HTLV-1 protein: the HTLV-1-binding bZIP factor, or HBZ (see discussion below). Down-modulation of MHC-I-restricted antigen presentation is mediated by the viral protein p12I, which sequesters the MHC-I heavy chain (MHC-I α chain) in the endoplasmic reticulum (ER) and prevents it from binding β2-microglobulin. In time (20 to 60 years), Tax-dependent cell proliferation of escape mutants leads to low-grade ATL (chronic or smoldering-type ATL). This stage is associated with a slight increase in white blood cell counts, occasionally accompanied by skin lesions, lymphadenopathy, and hepatosplenomegaly. At this point, infected individuals are past the carrier state and progress to aggressive ATL within a few years. From here on end, Tax protein expression keeps waning and eventually ceases completely via the previously described mechanisms and in response to HBZ. HBZ suppresses Tax-mediated proviral transcription and presumably plays a key role in leukemogenesis, as it promotes T-cell proliferation, and its absence inhibits the proliferation of ATL cells. As opposed to most viral genes that are located on the coding DNA strand (i.e., positive sense strand under the control of the 5’-LTR regulatory element that eventually becomes silenced due to the genetic and epigenetic alterations previously discussed in this paragraph), HBZ is encoded on the complementary negative sense DNA strand and is under the control of a functional, hypomethylated, 3’-LTR promoter. HBZ is, therefore, continuously expressed throughout the infection. At some point late into the infection then, after the infected lymphocytes have entirely escaped the CTL response and do not express Tax anymore, ATL cells have accumulated enough alterations in host tumor suppressor genes that these cells recapitulate the effects of Tax. Such alterations include genetic mutations in p53, deletions or mutations in p15INK4B, p16INK4A, p27KIP, pRb, and Fas, and altered expression levels of p21CIP, p27KIP, Bcl-xL, cyclooxygenase-2 (COX-2), FasL, Kruppellike factor-4 (KLP-4), Egr-3, and STAT-5 (signal transducers and activators of transcription-5) among others. This is called Tax-independent cell proliferation and is characteristic of aggressive ATL (acute or lymphoma-type ATL). At this stage, many cellular transcription factors are constitutively expressed (NF-κB, NF-AT, AP-1, STAT-5). ATL cells express a Treg phenotype (CD4+, CD25+), and consequently, ATL patients are extremely immunocompromised and particularly susceptible to opportunistic infections such as Pneumocystis jirovecii, Mycobacterium spp., Strongyloides spp., and human cytomegalovirus (HCMV). This stage is characterized by high numbers of ATL cells, frequent skin lesions, systemic lymphadenopathy, and hepatosplenomegaly. The median survival time (MST) at this stage is about 1 year. There are also genetic predispositions to ATL. These include polymorphic sequences of the promoter region of the tumor necrosis factor-α (TNF-α) gene that promote increased TNF-α production, as well as certain HLA alleles (HLA-A26, HLA-B4002, HLAB4006, HLA-B4801). Although ATL can be a devastating disease, it must be stressed that most HTLV-1 carriers do not progress to disease (only 1% to 5% do). HTLV-1 infection is diagnosed by the demonstration antibodies to HTLV-1 in the patient’s serum: screening by ELISA (particle agglutination assay is an alternative), confirmation by western blot (RT-PCR is an alternative when the western blot is indeterminate). ATL is diagnosed by (1) positive result for HTLV-1 infection, (2) hypercalcemia, (3) the detection of flower cells (CD3, CD4, CD7, CD8, and CD25 positive T lymphocytes with lobulated, flower-like, nucleus), and (4) monoclonal insertion of HTLV-1 proviral DNA in T lymphocytes. Prognosis for ATL is poor and multiple treatment strategies are used given the lack of optimal chemotherapy regimens. Antiretroviral Pharmacotherapy Lifelong treatment to control virus replication Resistance develops rapidly if antiretroviral agents are used improperly (NO monotherapy) In addition to efficacy, long-term convenience, tolerability, and safety are important to therapy selection Surrogate markers of treatment response ◦ Viral load (plasma HIV RNA concentration)↓ - The expected treatment outcome is an undetectable viral load (plasma HIV RNA < 50 copies/mL). ◦ CD4+ T-cell count↑- gradual increase that approaches normal The U.S Department of Health and Human Services recommends that everyone with HIV infection be treated with combination drug therapy Drug treatment for pre-exposure prophylaxis is also recommended for individuals at high risk of HIV infection. Supplemental Resources Tables adapted from Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Department of Health and Human Services. Available at http://aidsinfo.nih.gov/ Antiretroviral Agents Sites of Action of Antiretroviral Drugs These are the sites of action for some specific classes of antiretroviral drugs Maraviroc (CCR5 Inhibitor): Maraviroc is a CCR5 inhibitor that blocks the interaction between the viral envelope protein and the CCR5 co-receptor on the surface of host cells. This interaction is necessary for HIV to enter the host cell. By binding to CCR5, maraviroc prevents HIV from entering the cell and initiating the infection Enfuvirtide (Fusion Inhibitor): Enfuvirtide, also known as T-20, is a fusion inhibitor that acts at the entry stage of the HIV life cycle. It works by interfering with the fusion of the viral and host cell membranes, preventing the virus from entering the cell Nucleoside Reverse Transcriptase Inhibitors (NRTIs): NRTIs, like zidovudine and tenofovir, target the reverse transcriptase enzyme. They are incorporated into the growing viral DNA chain and cause premature termination, blocking the conversion of viral RNA into DNA. (Note: You are not required to know chemical structures.) Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs): NNRTIs, including efavirenz and nevirapine, also target reverse transcriptase but do so by binding directly to the enzyme and distorting its active site, inhibiting its function Raltegravir (Integrase Strand Transfer Inhibitor): Raltegravir is an integrase strand transfer inhibitor that targets the viral integrase enzyme. It prevents the integration of viral DNA into the host cell's genome, disrupting a critical step in the HIV life cycle Protease Inhibitors: Drugs like ritonavir and darunavir target the HIV protease enzyme. Protease is essential for cleaving viral polyproteins into their functional components, allowing the assembly of new virus particles. Protease inhibitors disrupt this process, preventing the production of mature and infectious viral particles These various classes of antiretroviral drugs are often used in combination, known as antiretroviral therapy (ART), to target multiple stages of the HIV life cycle simultaneously. This combination therapy is highly effective in suppressing viral replication, reducing the viral load, and helping individuals with HIV to manage the infection and maintain their immune health. Nucleos(t)ide Reverse Transcriptase Inhibitors (NRTI) Mechanism of Action NRTIs Nucleoside and nucleotide analoganalogsues must enter cells and be phosphorylated to generate synthetic substrates for reverse transcriptase. The fully phosphorylated analogues block replication of the viral genome both by competitively inhibiting incorporation of native nucleotides and by terminating elongation of nascent viral DNA because they lack a 3′hydroxyl group. NNRTIs induce a conformational change in the 3-dimensional structure of the enzyme that greatly reduces its activity, and thus, they act as noncompetitive inhibitors. (Do not bind to the active site They are active agains HIV-1 but NOT HIV-2. Nucleos(t)ide Reverse Transcriptase Inhibitors (NRTI) Chemistry/Antiviral Activit ◦ Analogs of nucleosides or nucleotide ◦ HIV-1 and HIV Pharmacokinetic ◦ Require intra-cytoplasmic activation via phosphorylation by cellular enzymes; al ◦ agents must be triphosphorylated (except tenofovir a nucleotide monophosphate analog which requires addition of two phosphates) Pharmacodynamic ◦ Competitive inhibition of reverse transcriptase; terminate elongation of nascent vira DNA because they lack a 3′-hydroxyl group ◦ Selective toxicity based on their affinity for DNA-polymerase gamma (mitochondrial enzyme) Resistanc ◦ Mutations in the HIV reverse transcriptase (can cause resistance to individual agents or entire class of NRTIs) Adverse Effect ◦ Lactic acidosis with hepatic steatosis (especially for zidovudine, stavudine and didanosine) Common and/or Severe Adverse Effects Associated with Specific NRTIs NRTIs with Hepatitis B Viral Activity Tenofovir, Lamivudine and Emtricitabin Most of the antiretroviral drugs are only used to treat HIV infection. The drugs listed above are exceptions. They are also used to treat hepatitis B infection and are usually included in treatment regimens for people who have HIV and Hepatitis B co-infection Lamivudine and Emtricitabine have an almost identical structure. The drugs should not be used together in a treatment regimen. If a patient develops resistance to lamivudine, then they will likely have resistance to emtricitabine as well. Non-nucleoside Reverse Transcriptase Inhibitors (NNRTI) *Rilpivirine and Etravirine are not on your drug list but may be encountered on external exams. Mechanism of Action NNRTIs NNRTIs induce a conformational change in the 3-dimensional structure of the enzyme that greatly reduces its activity, and thus they act as noncompetitive inhibitors. (Do not bind to the active site They are active agains HIV-1 but NOT HIV-2. Antiviral Activit ◦ HIV-1 onl Pharmacokinetics/Pharmacodynamic ◦ ◦ ◦ Does not require phosphorylation to be activ Non-competitive inhibition of reverse transcriptas Metabolism by the CYP45O syste Resistanc ◦ Mutations in the HIV reverse transcriptase; some mutations confer resistance to the entire clas ◦ No cross resistance with the NRTIs (some NRTI resistant viruses are more susceptible to the NNRTIs ◦ Rapid resistance (days or weeks) if given as monotherap Adverse Effect ◦ ◦ Rash (All NRTIs Drug interactions are an important consideration due to CYP450 metabolism Common and/or Severe Adverse Effects Associated with Specific NNRTIs Efaviren ◦ Neuropsychiatric symptoms – abnormal dreams, depression, suicide ideation, hallucinations and euphoria Antiviral Activit ◦ HIV-1 and HIV- Pharmacodynamic ◦ ◦ ◦ Competitive inhibitors of HIV aspartyl proteas Extensively metabolized by CYP3A Ritonavir most potent, used as a pharmacokinetic enhancer to “boost” other PI Resistanc ◦ Mutations in the HIV aspartyl protease (encoded by the pol gene); high resistance threshold, requires multiple mutations Adverse Effect ◦ ◦ Lipodystrophy syndrome: central obesity, peripheral fat wasting, fa deposition in the neck (buffalo hump), increased plasma lipids and insulin resistance is associated with the PIs ◦ Significant drug-drug interactions Protease Inhibitors (PI) *Darunavir, Fosamprenavir Nelfinavir, and Tipranavir are not on your drug list but may be encountered on external exams Ritonavir Pharmacology Pharmacokinetic ◦ Hepatic metabolism: CYP3A4 and CYP2D Pharmacodynamic ◦ ◦ Potent inhibitor of Cytochrome P450 3A4 (CYP3A4 Increases the plasma concentration and prolongs elimination of drugs that are CYP3A4 substrates. Reduces pill burden Clinical Use ◦ Pharmacokinetic enhancer/booster of other agents used in the treatment of HIV infection, NOT recommended as primary protease inhibitor. The dose of ritonavir need for boosting is sub-therapeutic for antiretroviral activity Adverse Effect Significant drug-drug interactions Lipodystrophy [Image placeholders: S21 Lipodystrophy] Lipoatrophy Fat wasting in the cheeks. Lipohypertrophy Fat buildup on the back of the neck between th shoulders. *Fat rearrangement is also associated with metabolic disease (hyperglycemia and hyperlipidemia) Common and/or Severe Adverse Effects Associated with Protease Inhibitor Entry Inhibitors Maraviroc Enfuvirtide Maraviroc Mechanism of Action Maraviroc Pharmacology Antiviral Activit ◦ ◦ CCR5-tropic (R5) HIVNo activity against CXCR4-tropic, dual or mixed strain Pharmacodynamic ◦ Maraviroc binds specifically and selectively to the host protein CCR5, one of two chemokine receptors necessary for entrance of HIV into CD4+ cell Pharmacokinetic ◦ ◦ Ora Hepatic metabolism: CYP3A Clinical Use ◦ Treatment of CCR5-tropic HIV-1 infection in treatment-experienced adul patient Resistanc ◦ A switch in tropism from CCR5 to CXCR4 confers resistance; mutation in gp12 that allows binding in the presence of maraviroc also causes resistanc Maraviroc Adverse Effects/Contraindications Hepatotoxicit CYP3A4 substrat ◦ Many potential drug-drug interaction ◦ Contraindicated in patients who are taking CYP3A4 inhibitors or inducers Enfuvirtide Pharmacolog Chemistry/Antiviral Activit ◦ ◦ 36-amino-acid peptid HIV- Pharmacokinetic ◦ ◦ Subcutaneous injectio Metabolism: proteolytic hydrolysis (no CYP450 Pharmacodynamic ◦ Binds to gp41 subunit of the viral envelope glycoprotein and prevents fusion to host cel Clinical Us ◦ HIV-1 infection in treatment-experienced adult patient Adverse Effect ◦ Injection site reaction; painful erythematous nodule Resistance ◦ Specific mutations in the enfuvirtide-binding domain of gp4 Integrase Inhibitors: Raltegravir *Dolutegravir and Elvitegravir are not on your drug list Raltegravir Mechanism of Action Raltegravir Pharmacology Antiviral Activit ◦ HIV-1 and HIV- Resistanc ◦ Resistance involves mutations in the integrase gen Pharmacokinetic ◦ ◦ Ora Hepatic metabolism; glucuronidation by UGT1A Pharmacodynamics ◦ Blocks the catalytic activity of the HIV-encoded integrase, thus preventing integration of virus DNA into the host chromosome Clinical Use ◦ Treatment of HIV infection in adults and children Raltegravir Adverse Effects Severe hypersensitivity reaction Drug-drug interaction Any drug the induces or inhibits UGT1A1 will alter the plasma concentration of raltegravir. Rifampin a potent inducer of the CYP450 enzymes is also an inducer of UGT1A1. Antiretroviral Therapy (ART) Combination drug therapy, usually three or more antiretroviral drugs (ARVs) for treatment of human immunodeficiency virus (HIV) infection Combination drug therapy is used to prevent the emergence of drug resistant virus Most recent guidelines from the Department of Heath and Human Services can be found at What Not to Use Antiretroviral Components NOT Recommended as Part of ART Regime Treatment Considerations Based on Specific Clinical Scenario Common and/or Severe Adverse Effects Associated with ART Study Questions 1. 2. 3. 4. 5. 6. Work through these questions to prepare for the in-class activity. Describe and contrast the disease dynamic curves (viral load, CD4 lymphocytes, CD8 lymphocytes, IgGs) of an HIV-1-positive individual treated with antiretrovirals and an HIV-1positive individual not treated with antiretrovirals. Compare and contrast the different risks associated with HIV transmission. Describe the maturation of the HIV particle and its relevance vis-à-vis the use of protease inhibitors in the treatment of HIV infections. Describe the mechanisms of CD4 depletion during the end-stage of HIV infection. Compare and contrast the clinical presentations of HIV-1/2 and HTLV-1, as well as the treatments associated with each. Answer to drug category practice question