Videoclase VIH parte 1

History and Origins of HIV

Introduction to HIV

• The class focuses on the Human Immunodeficiency Virus (HIV), dividing the discussion into two parts: history/origins, viral replication, epidemiology, and pathogenesis.

Origins of HIV

• Initial reservoirs for HIV-2 were identified in primates, specifically the Cercopithecus atys (Sooty Mangabey).

• Genetic analysis indicates that HIV-1 originated from simian immunodeficiency virus (SIV) found in chimpanzees and gorillas, tracing back to a single subspecies in Central Africa.

Geographic Distribution

• A map illustrates the geographic origins of both HIV-1 and HIV-2; with HIV-2 emerging from West Africa (Senegal, Guinea, Ivory Coast, Ghana) and HIV-1 primarily from Congo, Gabon, and Cameroon.

Transmission Mechanisms

• Phylogenetic analysis shows that human evolution of HIV began between 1910 and 1930. Transmission likely occurred through blood contact during hunting or butchering infected chimpanzees.

Early Evidence of Infection

• The oldest known sample with antibodies for HIV-1 dates back to 1959 from Arno Motulsky in Leopoldville (now Kinshasa), linked to an oral polio vaccine campaign that may have inadvertently spread the virus.

Emergence of the AIDS Epidemic

Natural Transfer vs. Epidemic Spread

• While natural transfer involved direct contact with infected primates' blood or secretions during various activities, questions arise about why AIDS emerged prominently only in recent decades.

Stages of Epidemic Development

• Two stages are identified: initial transmission from SIV to humans followed by epidemic establishment due to demographic changes in Africa throughout the 20th century.

Conditions for Rapid Spread

• Intermittent infections could have been contained until social conditions allowed rapid human-to-human transmission leading to the current epidemic state.

Geographical Spread Beyond Africa

Initial Cases Documented

• First documented cases of group M infection occurred around Kinshasa; spread began towards neighboring countries like Brazil and Uganda starting in 1958 due to refugee movements.

Role of Migration

• Post-independence conflicts led to increased migration across borders which facilitated further spread throughout Africa via truck drivers and laborers moving between regions.

Introduction of AIDS into Developed Countries

Haitian Connection

• Hundreds of Haitians involved in UNESCO programs returned home regularly after working in Congo between 1960–1975, introducing the virus from Africa back into Haiti.

Impact on Urban Centers

• The gay rights movement beginning in New York City around 1969 created environments conducive for sexually transmitted diseases among young adults across major cities like San Francisco and Los Angeles.

Official Recognition of AIDS

First Reported Cases

Overview of HIV and Its Characteristics

Understanding Retroviruses

• Human Immunodeficiency Virus (HIV) is classified as a retrovirus, which are RNA viruses that replicate through a DNA intermediate using reverse transcriptase.

• Lentiviruses, a subfamily of retroviruses, include medically significant viruses such as HIV types 1 and 2 (HIV-1 and HIV-2), and Human T-cell Lymphotropic Viruses (HTLV).

Historical Context of HIV

• In 1983, three viruses were proposed as causes of AIDS: LAV (Lymphadenopathy Associated Virus), HTLV type 3, and an arbovirus related to AIDS.

• Genetic comparisons revealed these belonged to the same virus family, leading to the classification of HIV under the Retroviridae family.

Types of HIV

• Two main types exist: HIV-1, which is responsible for the global pandemic, and HIV-2, endemic to Central and West Africa with lower transmissibility.

• While both types cause AIDS in humans, HIV-2 typically results in milder immunodeficiency compared to HIV-1.

Epidemiology and Origins

Transmission Pathways

• The epidemic began after simian immunodeficiency virus (SIV) infections from primates; hunters likely were the first infected group.

Geographic Distribution

• Different subtypes of HIV have distinct origins:

• HIV-2 originated in Equatorial Guinea,

• HIV-1 traces back to Cameroon, Gabon, and Congo between 1910–1940.

General Characteristics of Lentiviruses

Infection Patterns

• Lentiviruses establish latent infections with prolonged incubation periods; they can persist despite competent immune responses.

Disease Progression

• These viruses lead to multisystemic diseases characterized by aggressive replication within CD4+ lymphocytes over time.

Morphological Features of HIV

Structure Overview

• Morphologically, HIV is spherical with an icosahedral symmetry; it has a positive-sense single-stranded RNA genome approximately 100 nanometers in size.

Viral Components

• Key components include:

• Surface glycoproteins gp120 and gp41 forming complex gp160 for cell entry,

• A capsid protein p24,

• Essential enzymes like reverse transcriptase, integrase, and protease involved in viral replication.

Viral Interaction Mechanisms

Receptor Engagement

• The virus interacts with various receptors on host cells beyond CD4+, including:

• CCR5 (macrophage tropism),

• CXCR4 (T-cell tropism).

Understanding HIV Entry Mechanisms

Discovery of Co-receptors and Their Role

• The discovery of co-receptors CCR5 and CXCR4 was crucial for understanding how the HIV virus enters host cells.

• HIV primarily targets activated CD4+ T lymphocytes, with entry facilitated by the interaction between CD4+ T cells and the gp160 complex. However, this process requires the presence of chemokine co-receptors CCR5 or CXCR4.

Classification of HIV Strains

• HIV-1 strains are categorized into two groups: macrophage-tropic (M-tropic) and T-tropic strains. M-tropic strains infect macrophages and primary T lymphocytes but do not induce syncytium formation in vitro.

• Non-syncytium-inducing strains are predominant during early infection stages, have slow replication rates, and are believed to have a higher transmission potential. They mainly infect monocytes, macrophages, and CD4+ T lymphocytes.

Syncytium-Inducing Strains

• T-tropic strains infect established T cell lines and induce syncytium formation on CD4+ MT2 cell lines; these strains emerge predominantly in late-stage disease with rapid clinical progression.

• Dual-tropic viruses can utilize both CCR5 and CXCR4 co-receptors for cell entry, complicating treatment strategies as they evolve with disease progression.

Mechanism of Viral Entry

• The entry mechanism involves sequential interactions with two receptors: CD4 followed by either CCR5 or CXCR4. This process is illustrated through a three-dimensional model showing viral structures like gp41 and gp120 that facilitate membrane fusion necessary for viral entry into host cells.

• The binding of the envelope protein to the CD4 receptor induces conformational changes in gp120 that allow for further interaction with appropriate co-receptors, leading to final conformational changes in the envelope protein that expose fusogenic sequences essential for membrane fusion.

Biological Cycle of HIV

• The biological cycle begins when HIV enters a target cell via its sequential receptor interactions; this leads to internalization of the nucleocapsid after membrane fusion occurs between viral and cellular membranes.

• Following internalization, reverse transcription occurs where viral RNA is converted into DNA by reverse transcriptase; however, incomplete retrotranscription may occur if resting lymphocytes are not activated adequately due to dependency on nucleotide levels induced during cellular activation processes.

Integration into Host Genome

• Once synthesized, proviral DNA associates with various cellular factors forming a pre-integration complex transported to the nucleus where it integrates into the host genome as proviral form; about 90% of existing viral DNA remains unintegrated within circulating lymphocytes as a reservoir susceptible to integration upon adequate cellular activation.

HIV Infection and Its Mechanisms

Initiation of HIV Transcription

• The process of HIV infection begins with the transcription of the viral genome, specifically during the initiation phase which relies on cellular factors and occurs without viral proteins.

• NF-kB is a key cellular factor involved in transitioning from viral latency to reactivation; it regulates multiple genes related to immune recognition and activation.

Role of Immune Activation

• The expression of the Tat protein increases the transcription rate of the HIV genome, facilitating complete elongation of viral RNA.

• Viral RNA is synthesized as a single transcript that must be transported to the cytosol, regulated by a nuclear protein called Rev.

Viral Protein Processing

• After synthesis, viral proteins undergo processing before assembling into mature particles; this final maturation occurs during budding through the cell membrane via viral protease action.

Impact on Immune Cells

• HIV affects not only T cells but also various other immune system components, targeting diverse tissues and organs including central nervous system cells and intestinal cells.

Epidemiological Aspects of HIV/AIDS

Emergence of AIDS Pandemic

• The AIDS pandemic officially began on June 5, 1981, when five cases of Pneumocystis carinii pneumonia were reported among young homosexual men in Los Angeles.

• Initially considered low-pathogenicity germs affecting severely immunocompromised individuals, more cases linked to immunodeficiency emerged over time.

Geographic Spread and Characteristics

• Early cases were documented in major U.S. cities like Los Angeles, San Francisco, New York City, and Miami; characterized by opportunistic infections from normal microbiota leading to severe health issues.

Demographics Affected by AIDS

• Affected groups included homosexual men and intravenous drug users presenting with unusual tumors like Kaposi's sarcoma alongside progressive immune dysfunction.

Understanding Transmission Dynamics

Modes of Transmission

• Epidemiological data suggested an infectious agent causing immunodeficiency transmitted primarily through sexual contact, parenteral routes (e.g., sharing needles), and vertically (from mother to child).

Cultural Context in Research

• Recommended viewing: "And the Band Played On," a film from the 90s that contextualizes 80’s epidemiological research efforts surrounding HIV discovery amidst political conflicts.

Current Statistics on HIV/AIDS

Prevalence Trends

• Currently estimated at 39 million adults and children living with HIV globally; new case numbers have stabilized indicating a shift from epidemic to endemic status.

Treatment Access Impact

Transmission of HIV: Key Insights

Modes of Transmission

• The primary modes of HIV transmission include sexual contact, with anal receptive intercourse being the highest risk, followed by vaginal receptive and insertive intercourse.

• Other transmission routes include exposure to infected blood through percutaneous means or mucosal splash, which have lower probabilities compared to transfusions from infected sources (over 90%).

• Perinatal transmission can occur transplacentally during pregnancy, at birth, or through breastfeeding, with a transmission rate exceeding 15%.

Current Situation in Argentina

• In Argentina, approximately 1.4 million people live with HIV; about 13% are unaware of their status.

• The median age for diagnosis is between 33 and 35 years, indicating that most infections occur around the age of 20.

• Emphasis on sexual education in secondary schools is crucial for prevention efforts.

Demographics and Risk Factors

• There is a higher incidence of infection among men compared to women; however, transgender individuals show a significantly lower contagion rate.

• Nearly all new infections in both genders result from unprotected sexual relations, making this the predominant mode of transmission in the country.

Understanding Stigmas and Risk Behaviors

Misconceptions About Risk Groups

• Historically labeled as "risk groups," this terminology has perpetuated stigma and discrimination against certain populations affected by HIV/AIDS.

• It is essential to eliminate the term "risk groups" since anyone can contract HIV regardless of demographic factors; behaviors rather than group identity determine risk levels.

Behavioral Risks Associated with HIV Transmission

• Key risk behaviors include having multiple concurrent sexual partners and inconsistent condom use.

• A study indicated that condom usage reduced the risk of HIV transmission by 78% among heterosexual couples where one partner was positive.

Pathogenesis of HIV Infection

Immune Dysfunction Mechanisms

• The hallmark feature of HIV infection is immune dysfunction characterized by a decrease in CD4 T lymphocytes due to various mechanisms:

• Direct cytopathic effects leading to cell destruction.

• Indirect mechanisms causing CD4 T cell loss.

Homeostasis Disruption

• Altered homeostasis results from lymphocyte redistribution and viral particle accumulation in lymphoid organs leading to CD4 T cell sequestration.

• This phenomenon reflects normal immune responses rather than direct damage caused by the virus itself.

Alterations in CD4 Lymphocyte Homeostasis

Mechanisms of Lymphocyte Regeneration Blockage

• The alteration in homeostasis of CD4 lymphocytes is primarily due to a blockage in lymphocyte regeneration, where active viral replication inhibits the generation of new lymphocytes from central immune organs like the thymus and bone marrow.

Impact on Naive CD4 Lymphocytes

• A decrease in naive CD4 lymphocytes worsens the generation of new lymphocyte clones, complicating the replacement of clones destroyed by HIV.

Susceptibility of Activated T Cells

• Direct cytopathic effects preferentially destroy activated T cells, which have high levels of receptors (SR5), nucleotides, and ATP that facilitate complete retrotranscription of the viral genome.

Consequences for Immune Response

• The destruction predominantly affects activated CD4 lymphocytes rather than resting ones, leading to significant implications for infection pathogenesis.

Effects on Gut-associated Lymphoid Tissue (GALT)

• Most CD4 lymphocytes in GALT are activated due to extensive antigenic load from external microbial interactions; this leads to irreversible destruction during infection stages that does not recover with antiretroviral treatment.

Memory T Cell Dynamics

Memory T Cell Generation and Destruction

• Memory T cells arise from naive cells during antigen recognition; their destruction results in fewer specialized cells capable of recognizing foreign antigens, exacerbating immunodeficiency.

Activation and Recognition Process

• Upon immune activation against HIV antigens, highly effective memory T cells are generated but are also targeted for destruction upon activation, worsening viral escape from immune response.

Indirect Mechanisms of CD4 Destruction

Immune System Targeting Infected Cells

• Infected CD4 lymphocytes become targets for immune system mechanisms; they express viral peptides making them susceptible to cytotoxic recognition and destruction by CD8 T cells.

Apoptosis as a Destructive Mechanism

• Apoptosis serves as a controlled cell death mechanism that can be induced by various factors including chronic immune activation and toxic effects from viral proteins.

Pathways Leading to Apoptosis

Extrinsic and Intrinsic Pathways

• Apoptosis occurs via extrinsic pathways triggered by cytokine receptor binding or intrinsic pathways altering mitochondrial permeability due to stress signals.

Role of HIV in Inducing Apoptosis

• HIV may induce apoptosis through multiple mechanisms such as chronic immune activation and interaction with viral envelope proteins leading to increased expression of cytotoxic ligands.

Persistent Viral Replication Effects

Continuous Immune Activation

Understanding the Impact of HIV on Immune Function

Mechanisms of Immune Dysfunction in HIV Infection

• The differentiation disorder of CD8 lymphocytes specific to HIV leads to a lack of cytolytic capacity, essential for effective immune response. Immunological markers indicate an imbalance in effector cell generation and proliferation compartments.

• There is evidence suggesting early exhaustion or aging of the immune system due to extreme antigen overload during HIV infection. The gastrointestinal-associated lymphoid tissue (GALT) is damaged from primary infection, initiating translocation mechanisms.

• Bacterial translocation occurs when viable bacteria pass from the intestinal lumen to extraintestinal sites without mucosal integrity disruption, affecting mesenteric lymph nodes, blood, and other organs. Endogenous virus replication may also contribute to chronic immune activation.

• In early stages of infection, high levels of HIV replication likely cause direct destruction or apoptosis of CD4 T cells before an effective immune response develops. This destruction is particularly pronounced in GALT.

• Once cellular immunity is established, immunomediated destruction by CD8 clones occurs alongside immune exhaustion as infection progresses. Lymphocyte sequestration and thymic blockade are more prevalent during high viremia phases.

Antibody Response and Viral Escape

• The body mounts a strong antibody response against nearly all structural and regulatory proteins of HIV; however, neutralizing antibodies are produced at low levels and quickly face viral escape mechanisms.

• Neutralizing antibodies targeting gp41 and certain domains of gp120 have been identified but their production remains limited. Viral escape through mutation makes it difficult for these antibodies to provide consistent protection.

• Highly variable regions on the gp160 protein induce antibody synthesis that can be easily evaded by viral mutations. Additionally, the heavily glycosylated envelope creates complex sugar structures that hinder antibody access.

• New immunization strategies may involve using sugars in specific conformations to generate neutralizing antibodies against HIV's glycan shield.

Broadly Neutralizing Antibodies

• A subset of chronically infected patients known as elite neutralizers produce broadly neutralizing antibodies capable of effectively targeting diverse viral variants beyond their infecting subtype.

• Characterization of these antibodies' structure, mechanism, and neutralization epitopes is crucial for understanding how they function against various viral strains.

Cellular Immune Response Against HIV

• The antiviral cellular response involves different populations including CD4 helper T cells, CD8 cytotoxic T cells, and NK cells; with CD4/CD8 responses being critical for protection against HIV.

• Studies show that seropositive patients exhibit clonal expansion of cytotoxic CD8 lymphocytes with significant activity against infected cells.

• Beyond CD8 responses, specific CD4 responses play a vital role not only in initiating effective immune responses but also possess intrinsic antiviral activity themselves.

Additional Factors Influencing Immune Response

• Soluble factors such as complement components inhibit viral infections including HIV. Interferons also demonstrate antiviral properties while defensins produced by leukocytes offer protective effects against infection in vitro.

• Chemokines act as natural ligands competing with CCR5 and CXCR4 co-receptors for binding with HIV at mucosal surfaces or during synaptic spread within the immune system context.

These insights collectively illustrate the complex interplay between HIV infection dynamics and host immune responses while highlighting potential avenues for therapeutic intervention.

Understanding HIV Infection Dynamics

Initial Events in HIV Infection

• The initial infection by HIV occurs through sexual transmission, targeting dendritic cells and lymphocytes in the mucosal layers of the vagina and rectum, which are part of the gut-associated lymphoid tissue (GALT).

• GALT constitutes about 50% of the immune system and serves as a primary defense mechanism against pathogens in the gastrointestinal tract, which is highly permeable and constantly exposed to various microorganisms.

Viral Replication and Dissemination

• After initial infection, it takes approximately 2 to 6 hours for the virus to cross the mucosal barrier. Local spread can occur within 1 to 6 days, leading to dissemination into peripheral lymph nodes.

• By 72 hours post-exposure, viral dissemination into peripheral lymph nodes can be detected. This highlights the critical window for initiating post-exposure prophylaxis with antiretroviral medication ideally within one hour after exposure.

Immune Response and Window Period

• Following infection, systemic dissemination begins around one week later when viral load becomes detectable in blood. This marks a significant increase in viremia due to rapid viral replication.

• An immunological window period lasts approximately 4 to 12 weeks during which no specific humoral or cellular immune response is detectable despite high levels of viremia.

CD4 Lymphocyte Destruction

• During this early phase, there is massive destruction of activated CD4 T cells particularly within GALT. This destruction plays a crucial role in HIV pathogenesis.

• The inability to recover GALT leads to increased bacterial translocation and contributes to chronic immune activation and senescence.

Chronic Phase of HIV Infection

• In chronic HIV infection, an immune response generates specific antibodies and cytotoxic CD8 T cells that can control viral replication but cannot eradicate it from persistent reservoirs.

• The ongoing pressure from both the immune system and viral adaptation characterizes this chronic phase lasting years; however, continuous viral replication leads to gradual loss of immune control.

Immune System Deterioration

• Persistent viral replication stimulates continuous generation of escape variants while also exhausting the immune system's capacity through constant antigenic stimulation.

• Over time, this results in progressive loss of CD4 T cell function due to overwhelming antigen load leading towards premature aging of the immune system.

Clinical Manifestations at Advanced Stages

• Late-stage disease manifests clinically as opportunistic infections or tumors due to significant drops in CD4 counts alongside virological deterioration.

• As immunity wanes further with increasing viral loads, patients become susceptible to opportunistic pathogens culminating in AIDS syndrome characterized by severe immunocompromise.

Reactivation of HIV: Understanding Persistence and Treatment

Mechanisms of Viral Persistence

• Current treatments cannot eradicate HIV due to viral persistence mechanisms in target cells. Evidence is seen when antiretroviral therapy (ART) is interrupted, leading to a rapid increase in viral load.

• Ultrasensitive techniques reveal low-level replication (1-5 copies of RNA per milliliter) persists in all patients on treatment, indicating ongoing viral presence in certain reservoirs.

• The origins of these reservoirs are debated, with three non-exclusive possibilities proposed: treatment escape, persistent replication in long-lived cell types, or reactivation from latent reservoirs.

Prognostic Biomarkers

• Key prognostic biomarkers include CD4 T-cell counts and plasma viral load (RNA copies). CD4 counts reflect the degree of immunodeficiency and guide ART initiation and monitoring.

• Since 1995, plasma viral load measurement has been the most reliable predictor for infection progression and ART efficacy. High RNA levels indicate active replication and CD4 destruction.

Natural History of HIV Infection

• The natural history of untreated HIV infection can be divided into three phases: acute primary infection, clinical latency/chronic phase, and symptomatic AIDS phase.

Acute Primary Infection

• Characterized by active viral replication and widespread dissemination to lymphoid organs; clinically referred to as acute retroviral syndrome resembling mononucleosis.

• This initial stage lasts up to 12 weeks with two sub-stages: early viral dissemination peaking at high viremia without detectable antibodies (window period).

Immune Response During Acute Phase

• A specific immune response against HIV emerges during this phase but is insufficient for complete virus eradication. Antibodies typically appear between 2 to 12 weeks post-infection.

Clinical Latency Phase

• Following seroconversion, a clinical latency phase occurs lasting from 1 to over 15 years where individuals remain asymptomatic while the infection progresses unnoticed.

Understanding Early Symptoms of Immunodeficiency

Initial Symptoms of CD4 Lymphocyte Count Decline

• When the CD4 lymphocyte count drops below 500 cells per milliliter, constitutional symptoms may begin to appear. These include:

• Unexplained weight loss

• Night sweats

• Chronic diarrhea

• Oropharyngeal candidiasis

• It is crucial to recognize these symptoms as they can prompt a visit to a healthcare provider, typically a general practitioner or pediatrician rather than an infectious disease specialist.

Importance of Monitoring Symptoms

• Awareness of these early symptoms is essential for timely intervention and management.

• Patients often do not consult specialists at this stage, making it vital for general practitioners to be vigilant in identifying potential signs of immunodeficiency.

Severe Immunosuppression Indicators

Advanced Stages of Disease Progression

• The final stages of the disease occur when the CD4 lymphocyte count falls below 200 cells per milliliter.