HIV 2024 Session Objectives - Ingrid Herrmann PDF

Human Immunodeficiency Virus 1 HIV Session Objectives I. II. III. IV. V. VI. Describe the epidemiology of HIV emphasizing at-risk groups and transmission risk. Describe the taxonomy of HIV. Explain the replication cycle of HIV including important genes and proteins. Describe the clinical course of H...

Human Immunodeficiency Virus 1 HIV Session Objectives I. II. III. IV. V. VI. Describe the epidemiology of HIV emphasizing at-risk groups and transmission risk. Describe the taxonomy of HIV. Explain the replication cycle of HIV including important genes and proteins. Describe the clinical course of HIV from transmission to AIDS. Compare and contrast the laboratory identification techniques and assays used to ID HIV and their limitations List the behaviors considered high-risk for HIV transmission and how testing should be adjusted in these patients. Additional Clinical Objectives VII.Describe the natural history of HIV infection in terms of phases of the infection with associated clinical findings. VIII.Discuss the definition of AIDS including the common opportunistic infections and neoplasms. IX. Describe the clinical and pathologic features of HIV encephalopathy. Clinical-Pathology Readings n Readings § Robbins and Cotran Pathologic Basis of Disease, 10th ed. (ClinicalKey). ØChapter 6, Acquired Immunodeficiency Syndrome, pp. 247-259. See Clinical Manifestations section of PowerPoint presentation for emphases. ØChapter 28, Human Immunodeficiency Virus, p. 1267. § Rubin’s Pathology: Mechanisms of Human Disease, 8th ed. (LWW Medical Education Library), ØChapter 32, HIV Encephalopathy “One can think of the middle of the twentieth century as the end of one of the most important social revolutions in history, the virtual elimination of the infectious disease as a significant factor in social life” Dr. Frank Burnet, 1962 Nobel Prize winner (Immune tolerance) Between 1980 and the early 90s, death due to infectious disease rose 58%! Human immunodeficiency virus (HIV) n In 1981, previously healthy homosexual men were diagnosed with opportunistic infections/rare cancers: P. jiroveci and Kaposi’s sarcoma. n Outbreaks were initially centered around Los Angeles, San Francisco, and New York. n All patients were suffering from severe immunodeficiencies and were acutely susceptible to opportunistic infections. Human immunodeficiency virus (HIV) n Originally called Gay-Related Immune Deficiency (GRID), this mysterious disease later appear in other demographics: ØIV drug users ØHemophiliacs ØBlood transfusion recipients ØSexual partners of patients with the disease ØChildren born from mothers with the illness Because of the broadening range of patients, the disease was renamed to acquired immunodeficiency syndrome (AIDS) Human immunodeficiency virus (HIV) HIV-1 and 2 Origins There are two HIV types: HIV1 and HIV-2 n Each possess multiple groups: ØHIV-1: M,N,O,P ØHIV-2: A-I n Globally, HIV-1 group M is the most common cause of the pandemic HIV n HIV-2 is less virulent than HIV-1 and is predominantly found in West Africa n HIV-1 and 2 Origins n HIV-1 and HIV-2 were transmitted to humans independently through human/primate contact. ØHIV-1 emerged from a chimpanzee/gorilla SIV ØHIV-2 originated from sooty mangabeys SIV n Hypothesized that bush meat hunting transferred the virus from primates to human hunter(s) (~1920’s) HIV-1 and 2 Origins n From Kinshasa (1920s), HIV-1 spread outward: ØPopulation density in Kinshasa allowed it to adapt to humans ØBooming sex trade industry ØTransportation hub with relatively high traffic volume (roads, railways, rivers, etc.) n From Kinshasa in the 1920’s, HIV-1 spread for 60 years ØReached Haiti in the 1960s ØHigh traffic volume between colonial Democratic Republic of Congo and Haiti ØRecognized in the U.S. in the early 1980s, but was probably present for decades (1960s, 1970s) before recognition HIV in the US n n n More than 1.2 million people in the US are living with HIV; 1 in 8 people infected with HIV are unaware they have the disease. From 2005 to 2014, the annual number of new HIV diagnoses declined 19%. Gay and bisexual men, particularly young African American gay and bisexual men, are at the highest risk for HIV infection. CDC currently has data through 2021 In 2021, 36,136 peoplea received an HIV diagnosis in the United States (US) and dependent areas. n From 2017 to 2021, HIV diagnoses decreased 7% overall in the US and dependent areas. n https://www.cdc.gov/hiv/statistics/overview/ataglance.html n HIV in the US: Geography n The rates of HIV and AIDS diagnoses are the highest in the South (53% of all total cases, 2019). n By the end of 2015, 86% of people living with HIV knew they were HIV-positive. But 12 out of 17 Southern states fell below this mark. n Linking people to care within 3 months after an HIV diagnosis improves their health and reduces the risk of transmission. The majority of states with the lowest levels of linkage to care were in the South. n In some Southern states, people living with diagnosed HIV are 3 times as likely to die as those living with HIV in some other states. Lifetime Risk of HIV Diagnosis, by State Global HIV Rates (2021) n Since the beginning of the AIDS epidemic, 84.2 million people have been infected. Ø1.5 million new infections in 2021. n 40.1+ million people have died of AIDS-related complications. n Overall, it is estimated at 0.7% of adults age 15–49 years worldwide are living with HIV. n Substantial variation exist in HIV rates by region; Sub-Saharan Africa is the most severely affected. ØIn Sub-Saharan Africa, 1 in 25 adults are HIV positive ØSub-Saharan Africa account for two-thirds of all HIV cases worldwide Viral Transmission n Exchange of body fluids, which means… ØSexual » Risk: Much higher in homosexual males and African Americans » Among heterosexual, women are at a higher risk than men » Increased risk if other STD are present, even if non-ulcerative STD » Circumcision of males is protective ØParenteral » Exposure to infected blood or blood products » Sharing contaminated needles (injecting drug users) » Transplantation of infected tissues or organs ØOccupational » Exposure to body fluids during health care delivery – universal precautions important – never make assumptions about someone’s level of risk Viral Transmission (con’t) n Vertical Transmission ØMother to fetus or newborn » Can be in utero or perinatal » Risk: transmission in 1/3 of births if no preventative treatment provided » Increased risk with high viral load of mother, traumatic birth » Antiretroviral drugs in both mother and baby have reduced this risk to close to zero ØBreast Feeding » Breast milk has maternal lymphocytes that can be infected and transmit » Antiretroviral drugs have lowered this transmission risk by lowering viral load in mother Retroviral Subfamilies n Retroviruses have seven genera, two of which are medically significant. Characteristics of Retroviruses n HIV is a retrovirus (Retroviridae) and is a member of the lentivirus genus. Common characteristics of lentiviruses include: Characteristics of Retroviruses n Retroviruses transcribe RNA to DNA (therefore ‘retro’) ØRetroviruses contain reverse transcriptase, which coverts viral RNA into DNA (the opposite of transcription) ØThe viral DNA genome is then inserted into the host DNA ØReverse transcriptase cannot proofread, thus the rate of mutation is incredibly high in retroviruses n All retroviruses have 3 genes (env, gag, pol). Lentiviruses are more complex retroviruses and have 6 additional genes as well (HIV-1: 9 total genes). General Structure of HIV n HIV general structure: ØTwo copies of ssRNA ØReverse transcriptase ØIntegrase ØProtease ØCapsid consisting of p24 protein ØInner membrane (p17 matrix) ØOuter lipid bilayer membrane (from host cell) ØTwo major envelope proteins: gp120 and gp41 Replication Cycle n HIV binds the CD4 molecule (which is present predominantly on CD4 T cells and macrophages) thru gp120 (envelope protein) n This causes a confirmation change in gp120, which then binds to a co-receptor present on cells: ØCCR5: receptor for chemokines RANTES, MIP-1α, and MIP-1β ØCXCR4: the receptor for chemokine SDF-1 n In addition, other receptors may bind the HIV virus and allow it to infiltrate tissue: DC-SIGN (dendritic cells), integrin α-4 β-7 (gut), and CCR2 (monocytes). HIV cell membrane fusion n n Binding of gp120 to its receptor (CD4) and co-receptor (CXCR4, CCR5) causes a conformational change in gp41, which draws HIV tightly to host cells. Fusion with the host cell then occurs. First HIV Cure n n n n n Timothy Ray Brown (“Berlin patient”) was diagnosed with HIV in 1995. Later he was diagnosed with acute myeloid leukemia. Radiation, chemotherapy, and a bone marrow transplant was utilized to treat the cancer. Brown received a BMT from a patient who had a homozygous mutation in CCR5: CCR5Δ32. Individuals with this mutation are highly resistant to HIV infections and rarely advance to AIDS. HIV Life Cycle After fusion with the host membrane, the capsid enters cells n Capsid ‘uncoats’, releasing viral RNA n Viral RNA is single stranded, but there are two copies of it Having 2 copies allows for genetic recombination between the strands Viral RNA is reverse-transcribed into DNA by reverse transcriptase n Viral dsDNA is transported into nucleus and integrated into host chromosome n ØIntegration into the chromosome requires integrase ØIntegrase cuts the chromosome, inserts the viral DNA and seals the chromosome back up ØViral genome is now called the PROVIRUS HIV Life Cycle Retroviral PROVIRUS is now sitting permanently in the host genome n When the virus is activated: n ØViral genes are transcribed into mRNA as if they were normal genes ØmRNA is translated into polyproteins ØViral protease chops these up into proteins ØViral RNA is packaged, transported to the membrane Ø‘Buds’ out and is released from the cell n Infection is lytic for the T cells, but not macrophages or dendritic cells HIV-1 Genes n All retroviruses have 3 core structural genes: Øgag, pol, env ØEach of the 3 structural genes is transcribed as one mRNA, then translated as one polyprotein, then separated by viral protease n Lentiviruses are more complex than most retroviruses and have additional genes: ØIn addition to gag, pol, env, HIV-1 has 6 additional genes (9 total) Ø15 total proteins are encoded Gag and Env Genes n Gag gene (gag) codes for HIV structural proteins: ØMatrix protein (MA), capsid protein (CA), nucleocapsid protein (NC) n Env gene (env) codes for envelope proteins responsible for viral fusion to host cells Øgp120: contains binding domains responsible for virus attachment to the CD4 molecule and coreceptors Øgp41: contains a transmembrane domain that anchors the glycoprotein in the viral envelope and a fusion domain that facilitates viral penetration into target cells Polymerase Gene (Pol) n Polymerase gene (Pol) codes for 3 essential proteins: ØReverse transcriptase » Converts single stranded viral RNA into double stranded DNA ØIntegrase » Integrates viral DNA into host chromosome ØProtease » Cleaves the polyproteins into separate proteins after translation n Each of these proteins are targets for antiretroviral therapy because they are each unique to the virus and essential for viral replication! Clinical Manifestations Pathogenesis: White Blood Cell Dysfunction HIV Infection leads to decrease in CD4+ T cells which can result in opportunistic infections or neoplasms. n Other components of the immune system (e.g. WBC’s) are affected. n Natural History/HIV Infection Progression After the primary infection, HIV disease progression can be broken down into 3 general phases: I. Acute HIV Infection II. Chronic Phase - Clinical latency III. Crisis - Symptomatic disease (Including AIDS) Figure 6.43A Natural History/HIV Infection Progression I. Acute Phase » 40-90% (Robbins and Cotran) of patients experience an acute clinical syndrome (acute retroviral syndrome) typically 3-6 weeks after the primary infection that resolves in 2-4 weeks. » Symptoms are suggestive of a mononucleosis-like illness » Neurological symptoms may be present » Suppression of CD4 T cells develops » High levels of viremia also present » During the initial weeks of the infection, the virus seeds in lymphoid organs throughout the body Natural History of HIV Infection Note the early stages of the infection (i.e. prior to clinical latency. n Correlate with Robbins and Cotran Fig. 6.43 and the above discussion. n Clinical Latency and AIDS stages follow. n Robbins and Cotran Fig 6.42 HIV Infection Progression II. Chronic Phase/Clinical latency Ø Lymph nodes and Spleen are sites of continuous HIV replication and cell destruction. Ø Few or no clinical manifestations are present (i.e. clinical latency) Ø After the initial infection, the host begins to produce antibodies against the infection (seroconversion). Viral titers can decline. Ø CD4 counts decline with time with waning of host defense. Viremia can then increase with time. Ø On average, patients can remain in this phase for 7-10 years without treatment. However, rapid progressors progress faster. Others are considered long-term nonprogressors. Ø The number of number of HIV RNA copies in plasma directly correlates with long-term disease progression. Ø See Robbins and Cotran Fig 6.43A. HIV Infection Progression III.Symptomatic disease Ø Although minor opportunistic infections can occur in the chronic phase of infection, the final phase is progression to AIDS with a increase in viral load and in severe, life-threating clinical disease Ø Symptoms can appear at any time, but the most threatening occur when CD4+ T cell counts decline to significantly low levels. See Robbins and Cotran Table 6.15. Ø A diagnosis of AIDS occurs when one of the two conditions are met: » A CD4 T cell count