Acquired Immunodeficiency Syndrome

Slide 1 · Acquired immunodeficiency syndrome

Human immunodeficiency virus (HIV) causes a progressive acquired immunodeficiency.

Failure of immune defense permits opportunistic infections, selected neoplasms, and neurologic disease.

The clinical phenotype reflects viral replication, loss of CD4⁺ T cells, and incomplete immune control.

Dr Abu Suraih Sakhri

MBBS, MD (Pathology)

www.abusuraihsakhri.com

Slide 2 · Learning objectives

Explain major HIV exposure routes and determinants of transmission.

Identify HIV structural components and the steps of infection.

Connect cellular immune injury with clinical progression, pathology, and opportunistic disease.

Distinguish the effect of antiretroviral therapy from eradication of the viral reservoir.

Slide 3 · HIV infection and AIDS are not synonymous

HIV acquisition and establishment

Chronic infection with immune injury

Advanced CD4⁺-cell depletion

AIDS-defining disease

Untreated HIV may progress to AIDS; Effective therapy profoundly alters the course.

Slide 4 · The hallmark is defective cell-mediated immunity

Progressive loss of CD4⁺ helper T cells undermines immune coordination.

Surviving T cells also have functional abnormalities.

Macrophages, dendritic cells, and B-cell responses are affected.

Immunodeficiency is broader than a low circulating CD4⁺ count alone.

Slide 5 · Three major consequences of immunodeficiency

Domain

Biologic explanation

Representative manifestation

Infection

Poor control of opportunistic and latent microbes

Pneumocystis pneumonia; cryptococcosis

Neoplasia

Reduced immune surveillance of oncogenic viruses

Kaposi sarcoma; B-cell lymphoma

Nervous system

HIV-related neuroinflammation and secondary disease

HIV-associated neurocognitive disorder

Organ involvement can be direct, indirect, or opportunistic.

Slide 6 · AIDS is a major global disease burden

A very large worldwide population living with HIV.

’s 2021 reference period, the distribution was especially concentrated in Africa.

Population estimates are time-dependent and must not be treated as current surveillance figures.

Slide 7 · Antiretroviral therapy reshapes the epidemic

ART suppresses replication, limits progression, and reduces mortality.

Effective therapy also decreases transmission, including vertical transmission.

Persistent HIV infection and inequitable access remain important public-health challenges.

Slide 8 · Three principal modes of HIV transmission

Sexual exposure to infectious secretions

Parenteral exposure to contaminated blood

Vertical transmission during gestation, birth, or breastfeeding

Transmission requires a biologically plausible exposure to HIV-containing material.

Slide 9 · Sexual transmission: Mucosal acquisition

Sexual transmission is the predominant route worldwide discussion.

Virus may cross damaged mucosa or interact with susceptible mucosal immune cells.

CD4⁺ T cells and dendritic cells help establish the infection at entry sites.

Slide 10 · Other sexually transmitted infections amplify risk

Ulcerative sexually transmitted disease can compromise mucosal barriers.

Inflammation recruits activated susceptible target cells into mucosal tissue.

Syphilis, chancroid, herpes, gonorrhea, and chlamydia are cited as cofactors.

Slide 11 · Blood-borne transmission requires direct inoculation

Sharing needles and syringes can transfer HIV-infected blood.

Contaminated transfused blood or blood products and organs can transmit HIV.

Improved donor screening and safer blood products dramatically reduced transfusion-associated infection.

Slide 12 · Transmission pathways versus nonroutes

Exposure pathway

Transmission interpretation

Blood or infectious sexual secretions contacting susceptible tissue

Biologically plausible transmission route

Needlestick exposure to infected blood

Recognized occupational route; uncommon

Casual household, school, or workplace contact

Does not transmit HIV

Insect bites

Not a meaningful mode of HIV transmission

Avoid stigmatizing nontransmission contact.

Slide 13 · Vertical transmission has distinct windows

In utero: Transplacental infection before delivery.

Intrapartum: Exposure during delivery.

Postpartum: Exposure through breast milk.

Maternal viral burden and immune impairment influence risk in untreated infection.

Slide 14 · Maternal HIV and pediatric infection

Maternal infection with replicating HIV

In utero, delivery-related, or breastfeeding exposure

Infant HIV acquisition without effective prevention

Major reductions in vertical transmission with maternal ART.

Slide 15 · Occupational infection: Rare but consequential

Percutaneous injuries and contact of infected blood with nonintact skin can transmit HIV.

Transmission is much less efficient than many other blood-borne viral infections.

Prompt antiretroviral post-exposure intervention.

Slide 16 · Exposure categories are not personal identities

Risk is determined by exposure routes and infectiousness, not by membership of a social group.

Regional patterns of sexual and parenteral transmission differ.

Historical United States case proportions are time-specific, not timeless risk estimates.

Slide 17 · HIV-1 and HIV-2: Related lentiviruses

Feature

HIV-1

HIV-2

Phylogeny

Human lentivirus

Related human lentivirus

Geography in Robbins

Most common in US, Europe, central Africa

Prominent in western Africa and India

Clinical result

Can produce AIDS

Can produce a similar disease

The subsequent molecular discussion primarily concerns HIV-1.

Slide 18 · HIV is an enveloped RNA retrovirus

HIV belongs to the lentivirus family.

The core contains two RNA copies plus viral reverse transcriptase, integrase, and protease.

A host-derived lipid envelope carries gp120 and gp41, which mediate cell entry.

Slide 19 · Anatomy of the HIV-1 virion

Gp120 / gp41: Attachment and fusion

Lipid envelope: Host-cell derived

P17 matrix beneath envelope

P24 protein forms capsid

RNA genome + viral enzymes

Slide 20 · Structural proteins and enzymes

Component

Principal role

gp120

Binds CD4 and chemokine coreceptor

gp41

Mediates envelope fusion

p24

Major capsid protein

p17

Matrix beneath lipid envelope

Reverse transcriptase / integrase / protease

DNA synthesis / integration / virion maturation

These functions explain major mechanistic therapeutic targets.

Slide 21 · HIV genome: Canonical and accessory functions

Long terminal repeats contain sequences regulating viral gene transcription.

Gag and pol encode precursors of structural and enzymatic proteins.

Env encodes envelope glycoproteins.

Regulatory and accessory genes include tat, rev, vif, nef, vpr, and vpu.

Slide 22 · Cell entry requires two receptor interactions

Gp120 attaches to CD4

Gp120 engages CCR5 or CXCR4

Gp41 exposes fusion peptide

Membrane fusion delivers viral core

CD4 binding alone is insufficient for productive viral entry.

Slide 23 · Chemokine coreceptors and viral tropism

Viral phenotype

Coreceptor

Typical preference

R5 / M-tropic

CCR5

Monocyte–macrophage lineage; common early

X4 / T-tropic

CXCR4

T cells; may expand during progression

Dual tropic

CCR5 and CXCR4

Can use either coreceptor

Tropism describes receptor usage, not an absolute cell restriction.

Slide 24 · Host CCR5 variation illustrates receptor dependence

Some inherited CCR5 variants impair infection by CCR5-dependent HIV strains.

Resistance to R5 HIV is not equivalent to protection from every possible HIV isolate.

Host genetic susceptibility is one component of a much broader host–virus interaction.

Slide 25 · From viral RNA to integrated provirus

Viral RNA enters the cell

Reverse transcriptase generates viral DNA

Integrase embeds proviral DNA in host genome

Host transcription machinery may express HIV

Integration creates a durable molecular basis for persistence.

Slide 26 · Latency and productive infection are distinct

Integrated proviral DNA may persist without substantial viral gene expression.

Cell activation can induce transcription and productive replication.

Productive infection generates virions and can injure or destroy infected T cells.

Slide 27 · Physiologic T-cell activation can activate HIV

Antigen or cytokine stimulation

NF-κB activation in the host cell

HIV LTR-driven transcription

Increased virus production

HIV exploits signaling normally used for immune responses.

Slide 28 · New infections can accelerate existing HIV replication

Intercurrent microbial infections stimulate inflammatory cytokine production.

T-cell and macrophage activation promotes HIV transcription.

Greater replication can fuel further immune cell loss and infection susceptibility.

Slide 29 · Viral production creates mature virions

Transcription and translation of HIV gene products

Assembly of viral components

Budding at the cell membrane

Protease-mediated maturation

The role of protease is viral-protein processing; Drugs can interrupt this step.

Slide 30 · Therapeutic targets map to viral biology

Viral process

Molecular target / general class

Entry / fusion

CD4–coreceptor interaction or fusion processes

Reverse transcription

Reverse transcriptase inhibitors

Integration

Integrase inhibitors

Protein processing

Protease inhibitors

This is a mechanistic framework, not a current prescribing protocol.

Slide 31 · The immune system is the principal viral target

CD4⁺ T lymphocytes are the major targets of HIV-associated immune failure.

Macrophages and dendritic cells also participate in infection and viral persistence.

The CNS is affected through infection of cells in the monocyte–macrophage lineage.

Slide 32 · Early dissemination begins at mucosal sites

Infection of susceptible mucosal CD4⁺ T cells

Capture or transport by dendritic cells

Replication within draining lymph nodes

Viremia and systemic lymphoid seeding

The earliest major tissue reservoir can lie outside peripheral blood.

Slide 33 · Mucosal memory T cells are especially vulnerable

Mucosal tissues contain a large compartment of memory CD4⁺ T cells.

Early HIV infection produces prominent loss of these susceptible cells.

This early tissue depletion may be underrepresented by circulating-cell measurements.

Slide 34 · Secondary lymphoid tissues sustain infection

Lymph nodes and spleen contain infected lymphocytes and virions.

Follicular dendritic cells can retain antibody-coated, infectious virions.

Ongoing replication in organized lymphoid tissue persists during clinical latency.

Slide 35 · Pathways to CD4⁺ T-cell depletion

Direct injury from productive infection

Activation-induced death of bystander cells

Inflammasome-associated pyroptosis

Failure of cell renewal and tissue architecture

Several mechanisms act together; Virus-induced cell death is central.

Slide 36 · Direct cytopathic injury is a major mechanism

Active viral production is associated with death of infected CD4⁺ T cells.

Memory cells within tissues are particularly susceptible.

Compensatory T-cell replacement can initially conceal extensive turnover.

Slide 37 · Bystander damage amplifies T-cell loss

Chronic immune activation can drive apoptosis of uninfected T cells.

Abortive infection may activate the inflammasome and pyroptotic cell death.

Cellular inflammatory products can recruit further susceptible cells.

Slide 38 · Lymphoid architectural damage compounds deficiency

Progressive disease disrupts germinal centers and follicular dendritic-cell networks.

Loss of organized tissue impairs immune-cell interactions and antigen responses.

Advanced lymphoid depletion accompanies severe systemic immunodeficiency.

Slide 39 · Functional abnormalities extend beyond T-cell number

Compartment

Immunologic abnormality

Consequence

T cells

Reduced Th1 responses and helper activity

Poor defense against intracellular microbes

B cells

Polyclonal activation but weak new responses

Impaired antibody protection

Macrophages

Impaired chemotaxis, phagocytosis, antigen presentation

Weakened innate and adaptive coordination

Qualitative defects help explain complex infection patterns.

Slide 40 · B-cell hyperactivation coexists with poor immunity

HIV-associated stimulation produces enlarged germinal centers and hypergammaglobulinemia.

Despite activation, effective responses to new antigens can be compromised.

Defective T-cell help and B-cell dysfunction contribute to impaired opsonization.

Slide 41 · Macrophages provide persistent cellular niches

Macrophages can remain viable despite carrying substantial viral material.

Infected macrophages in tissues outnumber infected circulating monocytes.

Monocyte-lineage cells may distribute virus to organs, including brain.

Slide 42 · HIV-related neurologic injury: Proposed mechanism

Infected monocytes enter CNS

Microglia/macrophages harbor virus

Inflammatory mediators and viral products accumulate

Neuronal dysfunction without direct neuronal infection

Indirect neurotoxicity as a major explanation; Mechanisms remain incompletely resolved.

Slide 43 · Untreated clinical course has three broad phases

Acute retroviral syndrome

Chronic clinical latency

Advanced immunodeficiency / AIDS

Clinical latency does not mean virologic inactivity.

Slide 44 · Acute infection: Systemic viral dissemination

HIV replication initially increases rapidly within lymphoid tissue.

Viremia distributes infection to lymphoid and other tissues.

Immune responses subsequently reduce, but do not eliminate, replication.

Slide 45 · Acute retroviral syndrome is nonspecific

Reported features include fever, sore throat, myalgia, fatigue, and weight loss.

Some patients develop rash, cervical adenopathy, diarrhea, or vomiting.

Clinical overlap with other acute viral illnesses means symptoms alone are not diagnostic.

Slide 46 · Partial antiviral control after acute infection

Initial high-level viremia

HIV-specific CD8⁺ T-cell and antibody responses

Decline to a persisting viral set point

Immune control reduces viremia but does not sterilize infection.

Slide 47 · The viral set point has prognostic meaning

Steady-state plasma HIV RNA reflects a host–virus equilibrium after primary infection.

Higher set points are associated with faster CD4⁺ decline and progression.

Individual trajectories vary, and ART changes the untreated natural history.

Slide 48 · Clinical latency masks ongoing pathology

Many individuals have few clinical symptoms during the chronic phase.

Lymphoid infection, replication, and CD4⁺ depletion nevertheless continue.

Persistent generalized lymphadenopathy can be a clinical manifestation.

Slide 49 · Progression to AIDS marks loss of immune containment

Viral replication becomes more difficult for host immunity to control.

CD4⁺ depletion crosses thresholds associated with serious opportunistic disease.

Severe infections, neoplasms, and neurologic syndromes dominate the presentation.

Slide 50 · Historical CDC CD4⁺ categories

CD4⁺ cells/µL

Category in Robbins discussion

≥500

Category 1

200–499

Category 2

<200

Category 3: most severe depletion

Historical surveillance framework; Not a substitute for current guidelines.

Slide 51 · Viral load and CD4⁺ counts answer different questions

Plasma HIV RNA quantifies circulating viral burden and response to suppression.

CD4⁺ count reflects the degree of helper T-cell depletion and infection vulnerability.

Interpretation requires clinical context and antiretroviral-treatment status.

Slide 52 · Advanced AIDS produces multisystem disease

Presentations may combine prolonged fever, weight loss, diarrhea, and generalized adenopathy.

Severe infections arise from microbes otherwise contained by healthy immunity.

Neoplasms and neurologic disorders may be presenting or concurrent diseases.

Slide 53 · Why opportunistic infections emerge

Latent microbes can reactivate when cellular immunity fails.

Low-virulence environmental organisms become invasive in susceptible hosts.

The dominant pathogens differ by geography, exposure history, and degree of immunosuppression.

Slide 54 · Pneumocystis pneumonia: Impaired cellular defense

Pneumocystis jirovecii is an important fungal opportunist in untreated AIDS.

Pneumonia may present with respiratory impairment in advanced immunodeficiency.

Its incidence declined markedly in populations responding to ART.

Slide 55 · Mucosal candidiasis can signal immune decline

Oral, esophageal, and genital candidiasis occur with impaired immune defense.

Oral thrush may herald advancing immunologic dysfunction.

Deeply invasive candidiasis is less characteristic without additional risk factors.

Slide 56 · Cytomegalovirus: Severe organ disease

CMV can produce retinitis, esophagitis, colitis, or disseminated infection.

Retinitis is associated with profound CD4⁺ depletion.

Effective ART reduced the incidence of severe CMV disease.

Slide 57 · Typical and atypical mycobacterial infections

Organism group

Typical clinical pattern in HIV

Mycobacterium tuberculosis

May reactivate or be acquired; pulmonary and disseminated forms

Mycobacterium avium complex

Disseminated infection particularly in advanced immunosuppression

Severely impaired T-cell immunity can blunt granulomatous responses.

Slide 58 · Central nervous system opportunists

Cryptococcus neoformans is associated with opportunistic meningitis.

Toxoplasma gondii can cause encephalitis with focal CNS lesions.

JC virus causes progressive multifocal leukoencephalopathy.

Slide 59 · Enteric infection and persistent diarrhea

Cryptosporidium and Cystoisospora may produce profuse watery diarrhea.

Other intestinal microorganisms, including enteric bacteria, can contribute.

Consequences include significant fluid loss and nutritional compromise.

Slide 60 · Why certain cancers increase in AIDS

Failure of virus-specific immune surveillance

Persistence or activation of oncogenic DNA viruses

Outgrowth of virus-associated neoplastic clones

Different tumors involve different viruses and additional transformation events.

Slide 61 · Kaposi sarcoma is HHV-8 associated

Kaposi sarcoma is a vascular/spindle-cell neoplasm linked to HHV-8 (KSHV).

AIDS-related disease may involve skin, mucosa, lymph nodes, lung, and gastrointestinal tract.

Reduced HHV-8 control and local growth/angiogenic signals contribute to pathogenesis.

Slide 62 · Kaposi sarcoma: Specific morphologic clues

The lesion contains spindle-shaped cells and slit-like vascular spaces.

Inflammatory cells accompany proliferating spindle cells.

Histologic findings require correlation with context; Morphology alone is not a marker of HIV infection.

Slide 63 · B-cell lymphomas are enriched in HIV infection

Immunodeficiency permits emergence of aggressive B-cell lymphomas.

Some arise through EBV/HHV-8-associated viral oncogenesis.

Others may relate to chronic germinal-center B-cell proliferation and oncogenic rearrangements.

Slide 64 · Oncogenic viruses and HIV-associated tumors

Oncogenic virus

Illustrative HIV-associated lesion

HHV-8 (KSHV)

Kaposi sarcoma; primary effusion lymphoma

Epstein–Barr virus

Selected B-cell lymphomas; often HIV-associated Hodgkin lymphoma

High-risk human papillomavirus

Cervical and anal squamous malignancies

These relationships are not interchangeable diagnostic criteria.

Slide 65 · HPV-associated squamous neoplasia is clinically important

Reduced immune surveillance allows persistence of high-risk HPV.

HIV-associated cervical and anal squamous lesions may be more frequent.

Evaluation and prevention depend on appropriate specialty-specific protocols.

Slide 66 · HIV-related neurologic disease is multifactorial

HIV-associated neurocognitive disorder can occur without a dominant opportunistic lesion.

Neurologic symptoms may also reflect CNS infection or lymphoma.

Neuropathology must discriminate direct inflammatory consequences from secondary pathology.

Slide 67 · Lymph-node morphology evolves with infection

Early infection: Reactive follicles

Enlarged reactive follicles

Advanced disease: Lymphoid involution

Depleted follicles and disrupted network

Native schematic of lymph-node architecture — not histology

Slide 68 · Advanced AIDS may suppress typical inflammation

Profound CD4⁺ deficiency can reduce formation of well-organized granulomas.

Opportunistic microbes may be numerous despite a sparse inflammatory infiltrate.

Special stains may be needed when microorganisms are not evident on routine sections.

Slide 69 · Successful ART interrupts the pathogenic cascade

Combination antiretroviral drugs suppress replication

Viral RNA falls and immune loss slows

CD4⁺ cell counts may recover

Many AIDS-associated complications become less frequent

Suppression is not eradication of integrated provirus.

Slide 70 · Effective treatment does not erase proviral persistence

Infected cellular reservoirs can maintain integrated HIV DNA.

Stopping therapy may allow clinically important viral rebound.

Long-term HIV management therefore differs from a sterilizing cure.

Slide 71 · Immune reconstitution can unmask inflammation

Immune reconstitution inflammatory syndrome can follow initiation of ART in advanced disease.

Clinical deterioration may occur despite falling viral load and rising CD4⁺ count.

This paradox to an excessive response to persisting microbial antigens.

Slide 72 · Long-treated patients have broader morbidity

Effective ART has reduced classic opportunistic AIDS outcomes.

Cardiovascular, renal, hepatic, and neoplastic disease remain consequential.

Persistent inflammation, immune alterations, and treatment toxicities may contribute.

Slide 73 · Clinicopathologic interpretation: Three questions

Question

What to evaluate

Is there substantial immune impairment?

CD4⁺ status, infection history, treatment context

What lesion explains current symptoms?

Site-specific infection, neoplasia, or inflammatory process

What evidence identifies the lesion?

Morphology, organism studies, and relevant confirmatory testing

Do not diagnose AIDS from nonspecific lymph-node morphology alone.

Slide 74 · Clinical problem: Acute mononucleosis-like illness

A patient develops fever, sore throat, myalgias, rash, and adenopathy after a possible exposure.

The syndrome is compatible with acute HIV infection but is nonspecific.

Ask: Why may early immune response coexist with appreciable viral dissemination?

Slide 75 · Case interpretation: Early dissemination

Infected mucosal and lymphoid cells amplify HIV before complete antiviral control.

Viremia accompanies systemic symptoms and tissue seeding.

An immune response lowers the viral burden without clearing integrated viral DNA.

Slide 76 · Clinical problem: Progressive immune failure

An untreated patient with profound CD4⁺ depletion develops pneumonia, oral candidiasis, and focal neurologic symptoms.

Consider simultaneous opportunistic conditions rather than a single unifying organism.

Ask: What immune defect connects pulmonary, mucosal, and CNS susceptibility?

Slide 77 · Case interpretation: Cell-mediated immune failure

Deficient CD4⁺ T-cell responses compromise defense against fungi and intracellular microbes.

Different organ systems may be affected by distinct opportunistic pathogens.

A focused diagnostic assessment should identify the specific cause in each site.

Slide 78 · Core mechanisms to retain

HIV uses CD4 plus a chemokine coreceptor for entry and integrates into host DNA.

Replication and immune activation drive CD4⁺ T-cell death and progressive tissue damage.

Late immune failure produces characteristic patterns of infection, malignancy, and neurologic illness.

ART markedly alters outcomes but leaves persistent viral reservoirs.

Slide 79 · Selected source and scope

Robbins, Cotran & Kumar. Pathologic Basis of Disease, 11th edition (2026), chapter 6.

AIDS: epidemiology and HIV properties (p. 219–220).

Pathogenesis, natural history, clinical features, morphology, and treatment effects (p. 220–230).

Clinical guidelines and current surveillance estimates were not added to this source-restricted deck.