Pathogenesis of HIV Infection and AIDS

Slide 1 · Pathogenesis of HIV Infection and AIDS

From viral entry to multisystem immune dysfunction

Dr Abu Suraih Sakhri

MBBS, MD (Pathology)

www.abusuraihsakhri.com

Slide 2 · Learning objectives

Explain HIV entry through CD4 and chemokine coreceptors.

Trace reverse transcription, integration, latency, and productive replication.

Differentiate the mechanisms of CD4⁺ T-cell depletion.

Explain the reservoir and immune effects of infected myeloid and lymphoid cells.

Connect B-cell and CNS abnormalities to HIV pathogenesis.

Slide 3 · CD4⁺ T-cell injury drives AIDS immunodeficiency

HIV infection

CD4⁺ T cells are central viral targets

Cell death and dysfunction

Helper T-cell number and function decline

Immune network failure

Cell-mediated and humoral responses weaken

Clinical susceptibility

Opportunistic infection and neoplasia emerge

AIDS is chiefly an acquired defect in helper T-cell–dependent immunity; Infection of non–T cells adds further injury.

Slide 4 · HIV acts within several interacting cellular compartments

CD4⁺ T cells

Principal cells depleted by productive infection.

Macrophages

Longer-lived infected cells with impaired host-defense functions.

Dendritic cells

Capture or transfer virus and support dissemination.

CNS myeloid cells

Microglia and infiltrating macrophages link HIV to neurologic damage.

The disease cannot be understood solely from circulating CD4⁺ T-cell counts.

Slide 5 · Mucosal entry establishes infection in lymphoid tissue

Exposure

Virus encounters mucosa or enters blood

Local encounter

T cells, macrophages, and dendritic cells interact with HIV

Lymphoid seeding

Infection becomes established in lymphoid organs

Persistence

Active replication and latent infection coexist

Lymphoid tissues are sites of viral amplification, immune-cell injury, and persistence.

Slide 6 · Latent and productive infection have distinct fates

Latent infection

Integrated proviral DNA is transcriptionally silent.

Infected cells may survive for months or years.

Cells serve as a persistent viral reservoir.

Productive infection

Proviral RNA and viral proteins are expressed.

New virions assemble and leave the cell.

Extensive budding often accompanies cell injury and death.

The latent reservoir and ongoing productive infection are biologically different obstacles.

Slide 7 · The HIV virion contains an enveloped RNA core

RNA

Gp120

Surface glycoprotein; Binds CD4 and coreceptors

Gp41

Transmembrane glycoprotein; Drives fusion

P17 matrix / p24 capsid

Structural layers surrounding the genome

RNA and enzymes

RNA genome, reverse transcriptase, integrase, protease

Slide 8 · Gp120 and gp41 divide entry functions

Gp120: Attachment

External envelope glycoprotein.

Binds CD4, then CCR5 or CXCR4.

Coreceptor recognition follows CD4-induced conformational change.

Gp41: Fusion

Transmembrane envelope glycoprotein.

Exposes a hydrophobic fusion peptide.

Drives fusion of viral and host membranes.

Attachment and membrane fusion are separate, sequential entry steps.

Slide 9 · The HIV genome links genes to pathogenic functions

Genome regions shown as functional groups, not to physical scale

LTR

Gag

Pol

Vif

Vpr

Tat

Rev

Vpu

Env

Nef

LTR

Gag

Matrix, capsid, and nucleocapsid

Pol

Reverse transcriptase, integrase, protease

Env

Gp120 binding and gp41 fusion

Tat

Enhances viral transcription

Vif

Counteracts APOBEC3G

Vpr

Supports nuclear targeting in macrophages

Slide 10 · Viral proteins have distinct roles in the life cycle

Protein / region

Principal function in the source

Pathogenetic implication

gp120 / gp41

CD4–coreceptor binding / membrane fusion

Cell tropism and entry

Reverse transcriptase

RNA → proviral DNA

Enables DNA phase

Integrase

Proviral genome insertion

Persistence / latency

Vif

Counteracts APOBEC3G

Promotes productive replication

Vpr

Macrophage nuclear targeting

Replication in nondividing cells

Slide 11 · CD4 binding alone does not permit cellular entry

Gp120 contacts CD4

Primary receptor recognition

Gp120 changes conformation

Coreceptor site becomes exposed

CCR5 or CXCR4 binds

Second receptor requirement is fulfilled

Gp41 engages membrane

Fusion becomes possible

Coreceptor recognition is necessary in addition to CD4 attachment.

Slide 12 · Gp120–CD4 binding exposes a coreceptor site

Unbound gp120

Coreceptor-binding site not optimally exposed

CD4 engagement

Envelope undergoes conformational change

New receptor interface

Gp120 can recognize CCR5 or CXCR4

The order matters: Coreceptor binding follows CD4-triggered structural rearrangement.

Slide 13 · Coreceptor use defines the R5 and X4 phenotypes

Viral phenotype

Coreceptor

Predominant tropism

R5

CCR5

Monocyte / macrophage lineage (M-tropic)

X4

CXCR4

T-cell lineage (T-tropic)

R5X4

Both

Dual coreceptor usage

The phenotypes describe receptor use and associated cell preference, not separate HIV species.

Slide 14 · R5 strains predominate in many early infections

R5 (M-tropic) virus as dominant early in most infections.

CCR5 availability permits infection of susceptible mucosal and myeloid targets.

R5 predominance at transmission helps link mucosal infection to systemic establishment.

This is a population-level tendency, not an absolute rule for every individual.

Slide 15 · X4 emergence is associated with greater T-cell injury

Coreceptor phenotype shifts

X4 variants accumulate in some infections

Expanded T-cell targeting

More T cells and precursors become susceptible

Intensified CD4⁺ depletion

Cellular immunodeficiency can worsen

The source describes the X4 phenotype as particularly damaging to the T-cell compartment.

Slide 16 · T-cell and macrophage tropism are not identical

Activated / memory T cells

Express CD4 with suitable coreceptors.

Especially susceptible to productive replication.

Frequent cytopathic loss after extensive budding.

Macrophages

Express lower levels of CD4 with coreceptors.

Can support infection without cell division.

Relatively resistant to HIV cytopathic effects.

Tropism shapes both the cellular distribution of infection and the fate of infected cells.

Slide 17 · Gp41 fusion allows the HIV core to enter

CD4 + coreceptor binding

Receptor complex is assembled

Gp41 reconfiguration

Fusion peptide becomes exposed

Fusion-peptide insertion

Target membrane is engaged

Membrane fusion

Viral core gains access to cytoplasm

The envelope is not simply endocytosed as an inert particle; It actively mediates membrane fusion.

Slide 18 · Entry sequence: A mechanistic checkpoint map

1

Gp120 attachment to CD4

2

Gp120 coreceptor binding

3

Gp41 fusion-peptide exposure

4

Viral–cell membrane fusion

5

Genome delivery to cytoplasm

Every step occurs before reverse transcription and proviral integration.

Slide 19 · Chemokine occupancy may limit HIV entry

CCR5 and CXCR4 are physiological chemokine receptors.

Chemokine binding can sterically interfere with HIV attachment to coreceptors.

Tissue chemokine concentrations therefore may influence infection efficiency.

This mechanism highlights why coreceptor interactions are biologically consequential.

Slide 20 · CCR5 genotype modifies vulnerability to R5 infection

Two protective CCR5 alleles

Strong resistance to infection by R5 HIV isolates is described.

Protection is coreceptor-specific; It is not universal protection from all HIV phenotypes.

One protective CCR5 allele

Does not prevent AIDS after infection.

The source describes a tendency toward delayed disease onset.

The source’s ancestry-specific percentages are not needed to establish the receptor mechanism.

Slide 21 · HIV replication traverses RNA and DNA phases

1

Envelope-mediated entry

2

Reverse transcription

3

Proviral DNA integration

4

Host-driven viral transcription

5

Protein assembly and budding

Persistence depends on the DNA intermediate; Productive infection requires subsequent viral gene expression.

Slide 22 · Reverse transcriptase synthesizes proviral DNA

Viral RNA genome

Genetic information enters cell

Reverse transcriptase

RNA-templated DNA synthesis

Double-stranded DNA

Proviral genetic intermediate

Reverse transcription is the molecular transition that makes integration into host DNA possible.

Slide 23 · Integration converts HIV into a long-lived genomic infection

Proviral DNA

Reverse-transcribed HIV DNA

Nuclear access

Integration machinery reaches host genome

Integrated provirus

HIV DNA becomes part of infected-cell chromosomes

Long-term potential

Latency or renewed expression can follow

An integrated provirus may persist without production of infectious virions.

Slide 24 · Latency is transcriptional silence—not viral absence

Silent provirus

HIV DNA is integrated.

Little or no viral gene expression.

No ongoing virion production required for persistence.

Activated provirus

Cell activation induces transcription.

Viral RNA and proteins accumulate.

Production of virions can injure the cell.

A cell can contain HIV genetic material while producing no detectable infectious virus.

Slide 25 · Virus assembly and budding complete productive infection

Proviral transcription

Viral RNA is generated

Protein synthesis

Structural proteins and enzymes accumulate

Assembly

Genomic RNA is packaged with viral components

Budding / release

New virions leave the plasma membrane

The textbook associates sustained productive budding in CD4⁺ T cells with cytopathic injury.

Slide 26 · Gag and Pol processing supports virion function

Precursor / gene

Products highlighted in Robbins

Role

Gag polyprotein

p17 matrix, p24 capsid, p7 nucleocapsid, p6

Structural organization and RNA packaging

Pol polyprotein

Reverse transcriptase, integrase, protease

DNA synthesis, integration, maturation

Env precursor gp160

gp120 and gp41

Receptor binding and membrane fusion

Protease-dependent processing converts polyproteins into functional components.

Slide 27 · T-cell activation changes replication permissiveness

Naive / resting T cells

Relatively inefficient productive infection.

Active APOBEC3G can restrict viral DNA.

Less favorable environment for viral gene expression.

Activated / memory T cells

Greater permissiveness to productive infection.

APOBEC3G restriction can be reduced.

Activation-associated transcription factors favor viral RNA expression.

Susceptibility depends on cellular activation state, not simply CD4 expression.

Slide 28 · APOBEC3G is a cellular antiviral restriction factor

APOBEC3G active

Host cytidine deaminase

C → U editing

Mutations introduced into viral DNA

Replication defect

Further viral DNA replication is inhibited

This intrinsic defense is particularly relevant to restriction in resting T cells.

Slide 29 · Vif antagonizes APOBEC3G-mediated restriction

HIV Vif expressed

Viral accessory protein binds restriction factor

APOBEC3G degradation

Cellular proteolysis reduces antiviral activity

Improved permissiveness

HIV replication proceeds more efficiently

Host restriction and viral countermeasure operate on the same viral replication barrier.

Slide 30 · Activation of latently infected T cells can revive HIV

Antigen or cytokine stimulus

Physiological activation signal

Transcription-factor induction

Including NF-κB activity

HIV LTR activation

Integrated viral genes are transcribed

Virion production

Productive infection may kill the T cell

Normal immune activation can unintentionally trigger HIV expression.

Slide 31 · NF-κB links inflammation to viral transcription

Cell stimulation

Antigen / cytokine receptor pathways

IκB degradation

Inhibitory protein is removed

NF-κB nuclear entry

Transcription factor becomes available

HIV LTR binding

Viral gene transcription is stimulated

The HIV promoter uses a transcription factor normally mobilized for immune responses.

Slide 32 · The long terminal repeat responds to host activation

Two long terminal repeats flank the HIV genetic region

5′ LTR

HIV gene region / integrated provirus

3′ LTR

NF-κB and other host factors

Bind control sequences in HIV LTR

Tat protein

Enhances elongation of HIV transcription

Cell activation

Makes the host transcriptional environment permissive

A physiological immune-activation signal can become a viral transcription signal.

Slide 33 · Other infections can increase HIV replication

Concurrent microbial infection

Host immune response is activated

Cytokine release

TNF and other mediators rise

NF-κB signaling

HIV transcription is stimulated

Increased viral production

Additional susceptible cells may be infected

A response intended to eliminate other microbes may create opportunities for HIV amplification.

Slide 34 · Inflammation and HIV reinforce one another

HIV replication

Productive infection

CD4⁺ loss

Weaker host defense

Coinfection

Additional antigenic stimulation

Immune activation

Cytokines and NF-κB

Self-reinforcing

Cycle

This self-amplifying loop links immune deficiency with persistent immune activation.

Slide 35 · CD4⁺ depletion begins when loss exceeds replacement

Frequent cell injury

Direct and indirect cell death

Initial compensation

Lymphocyte renewal offsets some loss

Exhausted replacement

Regeneration cannot keep pace

Profound lymphopenia

Helper-cell compartment collapses

A deceptively slow fall in blood CD4⁺ counts can mask substantial tissue turnover.

Slide 36 · Productive HIV infection directly damages CD4⁺ T cells

Activated T cell infected

Efficient viral replication

Virion production

Repeated synthesis and budding

Direct cytopathic injury

Infected T-cell death

Cumulative effect

Progressive CD4⁺ depletion

Direct viral cytopathicity as a major mechanism of infected-cell loss.

Slide 37 · Most infected cells are not visible in peripheral blood

Blood compartment

Only a small fraction of infected cells may circulate.

Peripheral measurements can underestimate infected tissue burden.

Tissue compartment

Secondary lymphoid organs and mucosa contain many infected cells.

Tissue death is central to cumulative CD4⁺ loss.

Blood and tissue distributions should not be treated as interchangeable.

Slide 38 · Memory CD4⁺ T-cell loss impairs recall immunity

Memory cells in tissues

Preferential HIV infection and death

Loss of primed clones

Previously established immune responses weaken

Impaired recall responses

Susceptibility to previously encountered microbes rises

HIV depletes immune memory as well as total helper T-cell numbers.

Slide 39 · Activation-induced apoptosis removes uninfected cells

Persistent antigenic stimulation

HIV antigens and opportunistic infections

Repeated T-cell activation

Bystander cells receive activation signals

Activation-induced death

Apoptosis of cells without productive HIV infection

The number of dying T cells can exceed the number infected at a given time.

Slide 40 · Abortive HIV infection can elicit pyroptosis

Nonproductive infection

Abortive viral replication

Inflammasome signaling

Inflammatory cell-death machinery activates

Pyroptosis

Cell death releases inflammatory contents

Local amplification

New leukocytes are recruited

Pyroptosis can connect nonproductive infection to collateral inflammation.

Slide 41 · Pyroptosis may recruit more susceptible target cells

Abortive infection

Inflammasome activation

Pyroptotic injury

Inflammatory release

Cell recruitment

More local immune cells

Further exposure

More potential HIV targets

Self-reinforcing

Cycle

The source presents this as a potential contributor to the spread of infection.

Slide 42 · Damage to lymphoid organs weakens cellular interactions

HIV infection in nodes

CD4⁺ cells and other targets involved

Architecture disrupted

Normal tissue composition deteriorates

Immune contacts impaired

Antigen-driven cellular cooperation declines

Loss of lymphoid organization compounds the reduction in immune-cell numbers.

Slide 43 · Impaired T-cell maturation can compound depletion

Infection of progenitors or support cells

Direct or cytokine-mediated effects

Reduced thymic maturation

Fewer new CD4⁺ cells develop

Replacement deficit

Injury outpaces regeneration

Precursor and support-cell injury as possible additional mechanisms.

Slide 44 · Syncytia allow injury to spread between adjacent cells

Gp120 on infected cell

Envelope protein displayed on cell surface

CD4 on uninfected cell

Intercellular receptor engagement

Membrane fusion

Multinucleated syncytium forms

Cell death

Bystander loss without separate viral entry

The source associates this mechanism particularly with X4 T-tropic strains in culture.

Slide 45 · CD4⁺ T cells are depleted by parallel mechanisms

Mechanism

Direct cellular event

Distinct contribution

Productive infection

Viral cytopathic death

Loss of infected T cells

Activation-induced apoptosis

Death of uninfected activated cells

Bystander cell loss

Abortive infection

Inflammasome-associated pyroptosis

Inflammation and recruitment

Lymphoid / thymic injury

Disorganized organs; impaired precursors

Reduced immune maintenance

Syncytium formation

Fusion of infected and uninfected cells

Collateral cell death

Slide 46 · Surviving CD4⁺ T cells may also function poorly

Antigen-driven proliferation is diminished even before advanced symptomatic disease.

Th1-type responses are reduced and intracellular signaling may be defective.

Both qualitative dysfunction and numerical CD4⁺ loss contribute to immune deficiency.

The reduction of T-cell help compromises other leukocyte compartments.

Slide 47 · Reduced Th1 help compromises intracellular defense

HIV-related CD4⁺ dysfunction

Reduced Th1 responses

Altered macrophage activation

Cell-mediated defense is compromised

Intracellular microbes persist

Greater susceptibility to viral and intracellular infections

Mechanism—not simply low lymphocyte numbers—explains the pattern of opportunistic infections.

Slide 48 · Loss of CD4 help propagates across immune compartments

CD8⁺ responses

Reduced coordination of cellular antiviral responses.

B-cell responses

Defective help for effective new antibody formation.

Macrophage function

Altered signals and direct myeloid infection impair defense.

Lymphoid organization

Loss of tissue integrity disrupts multicellular immunity.

CD4⁺ lymphocytes act as immune-system coordinators rather than isolated effector cells.

Slide 49 · Long-lived memory cells sustain latent proviruses

HIV integration

Genomic viral DNA persists

Long-lived memory T cell

Infected cell survives for extended periods

Transcriptional latency

Little or no ongoing viral expression

Later activation

Productive replication can resume

Persistence of an integrated provirus explains why suppression of circulating virus does not erase infection.

Slide 50 · Follicular helper T cells form a reservoir niche

Germinal-center Tfh

CD4⁺ helper subset can be infected

Restricted CTL access

CD8⁺ cytotoxic cells are less abundant within follicles

Reduced clearance

Infected cells can evade immune elimination

Long-term persistence

Follicular compartment can retain virus

Anatomical positioning affects the efficiency of immune elimination.

Slide 51 · The major viral reservoirs use different mechanisms

Site / cell

How HIV persists

Why elimination is difficult

Memory CD4⁺ T cell

Integrated, transcriptionally silent provirus

Long-lived cells with minimal viral expression

T follicular helper cell

Infected cells within germinal centers

Relatively limited CD8⁺ CTL access

Macrophage

Infected, cytopathically resistant cells

Cell survival and viral retention

Follicular dendritic cell

Intact virus held on surface processes

Captured virions can remain infectious

Slide 52 · Macrophages permit HIV replication without division

Typical dividing T-cell environment

Activated cells are highly permissive.

Productive replication frequently leads to cell death.

Terminally differentiated macrophage

Cell division is not necessary for HIV replication.

Vpr is linked to nuclear import of the viral preintegration complex.

HIV-1 has an unusual capacity to establish infection in nondividing myeloid cells.

Slide 53 · Vpr facilitates nuclear entry in macrophages

Nondividing macrophage

Intact nuclear envelope remains a barrier

HIV Vpr function

Preintegration complex targets nuclear pores

Nuclear access

Viral DNA reaches integration machinery

Macrophage infection

Replication can occur without cell division

Vpr provides a mechanistic explanation for HIV replication in differentiated macrophages.

Slide 54 · Infected macrophages survive longer than many T cells

CD4⁺ T lymphocytes

Productive infection often cytopathic.

Rapid loss reduces longevity of infected cells.

Tissue macrophages

Often contain many virions in intracellular vesicles.

Release relatively small quantities of virus.

Resist cytopathic effects; Can serve as reservoirs.

Different infected-cell survival patterns diversify HIV persistence.

Slide 55 · HIV alters macrophage antimicrobial functions

Macrophage function

Abnormality described in AIDS

Host-defense consequence

Chemotaxis

Reduced

Impaired movement to sites of infection

Phagocytic / microbicidal activity

Reduced

Less effective microorganism clearance

Antigen presentation

Lower class II HLA; poor T-cell presentation

Weaker T-cell activation

Cytokine secretion

IL-1 reduced; TNF dysregulated

Distorted inflammatory coordination

Slide 56 · Monocytes can move HIV into distal tissues

Infected blood monocyte

Virus is carried by a motile host cell

Tissue migration

Monocyte enters organs including CNS

Macrophage differentiation

Virus persists or spreads locally

Microglial exposure

Resident CNS myeloid cells can become infected

Cell-associated trafficking adds a dissemination route beyond free virions.

Slide 57 · Mucosal dendritic cells can convey HIV to lymph nodes

Mucosal HIV contact

DC captures viral material

Migration to node

DC transports virus into lymphoid tissue

T-cell encounter

Virus may be transferred to CD4⁺ cells

Established infection

Regional lymphoid amplification follows

Dendritic cells can promote dissemination even when capture is not equivalent to productive infection.

Slide 58 · Dendritic-cell receptors can retain infectious HIV

HIV binding

Lectin-like receptor recognizes viral envelope

Virion retention

Intact virus is displayed on cell surface

CD4⁺ T-cell contact

Infectious virus is presented to target cells

DC-mediated transfer distinguishes viral capture from intracellular replication.

Slide 59 · Follicular dendritic cells retain virions externally

Anti-HIV antibodies bind virions

Immune complexes form

FDC Fc receptors engage

Antibody-coated particles are trapped

Virus persists on processes

Particles remain associated with germinal-center meshwork

Tfh cell encounters virions

Infection of passing CD4⁺ cells remains possible

Most FDC-associated particles are surface-bound rather than evidence of productive FDC infection.

Slide 60 · HIV perturbs B cells without directly infecting them

Chronic HIV-associated stimulation

Multiple indirect activation pathways

Polyclonal B-cell activation

Germinal-center B-cell expansion

Plasma-cell increase

Excess immunoglobulin production

Impaired specific responses

New pathogen-specific responses remain weak

The source separates B-cell activation from effective humoral immunity.

Slide 61 · Several pathways may drive polyclonal B-cell activation

EBV reactivation

EBV can polyclonally stimulate B cells.

Viral gp41

The source proposes B-cell growth and differentiation effects.

IL-6

Infected macrophage-derived IL-6 may promote B-cell proliferation.

Multifactorial activation

The source proposes several contributors rather than a single established cause.

These mechanisms are presented by the source as contributors, not exclusive alternatives.

Slide 62 · High immunoglobulin levels do not ensure protection

Polyclonal stimulation

Germinal-center hyperplasia.

Increased plasma cells.

Hypergammaglobulinemia and possible immune complexes.

Specific antibody failure

Poor de novo responses to new antigens.

Weak T-dependent and some T-independent responses.

Inadequate opsonizing antibody defense.

Quantity of serum immunoglobulin is not synonymous with protective specificity.

Slide 63 · Humoral failure impairs encapsulated bacterial clearance

Defective B-cell response

Poor production of effective new antibodies

Inadequate opsonization

Phagocytes recognize some pathogens poorly

Reduced bacterial clearance

Encapsulated organisms disseminate more readily

This vulnerability with Streptococcus pneumoniae and Haemophilus influenzae.

Slide 64 · CNS involvement centers on infected myeloid cells

HIV-infected monocytes

Virus crosses into CNS with infiltrating cells

Resident microglial infection

CNS myeloid compartment becomes involved

Inflammatory / viral mediators

Soluble factors affect neuronal function

HAND

HIV-associated neurocognitive disorder

The source treats neurological injury as predominantly indirect rather than widespread neuronal infection.

Slide 65 · Neuronal injury can exceed apparent tissue destruction

Where HIV is found

Infiltrating macrophages and resident microglia.

Neurons and astrocytes are not major sites of productive infection account.

How symptoms arise

Viral proteins may impair neural function.

Inflammatory mediators from infected microglia may contribute.

Clinical dysfunction can outweigh observed structural lesions.

This mismatch supports a soluble-mediator model of neurologic dysfunction.

Slide 66 · Proposed mediators of HIV-related CNS dysfunction

Proposed mediator

Source indicated

Pathogenetic interpretation

IL-1, TNF, IL-6

Infected / activated microglia

Neuroinflammatory signaling

gp41

HIV envelope protein

Nitric-oxide induction has been implicated

gp120

Soluble viral envelope glycoprotein

Direct neuronal toxicity has been postulated

Robbins explicitly characterizes the precise mechanisms of CNS injury as incompletely understood.

Slide 67 · An integrated view explains multisystem HIV injury

HIV infection

CD4⁺ T cells

Cell death and failed T-cell help

Macrophages / DCs

Persistent infection and impaired defense

B-cell dysregulation

Polyclonal stimulation with poor new responses

CNS myeloid cells

Indirect neuronal dysfunction

Combined loss of cellular immunity, antibody protection, and tissue homeostasis

Slide 68 · Mechanism predicts the immune defect

Dominant lesion

Functional consequence

Clinical correlation

CD4⁺ death / poor Th1 signaling

Weak cell-mediated immunity

Opportunistic intracellular infections

Loss of immune coordination

Reduced effective antibody responses

Susceptibility to encapsulated bacteria

Macrophage / DC abnormalities

Poor ingestion, presentation, and pathogen control

Additional vulnerability to infection

CNS myeloid infection

Indirect neuronal impairment

Neurocognitive symptoms

Slide 69 · Application: Why does coreceptor identity matter?

An HIV isolate infects CD4⁺ lymphocytes but requires CXCR4 rather than CCR5 for entry. A second isolate uses CCR5 predominantly.

Explain the mechanism:

Classify the two isolates using the source terminology.

Which isolate is associated with stronger T-cell tropism?

Why is CD4 binding alone insufficient?

Slide 70 · Application: Why can antibody levels be high but ineffective?

A patient with advanced HIV infection has marked polyclonal hypergammaglobulinemia yet develops recurrent infection by an encapsulated bacterium.

Explain the mechanism:

Which B-cell phenotype explains the increased immunoglobulins?

Why may newly generated protective antibodies still be deficient?

How does this lead to impaired bacterial clearance?

Slide 71 · Application: Why can HIV injure the CNS indirectly?

An HIV-infected patient develops cognitive dysfunction. Tissue analysis localizes most detectable HIV to macrophages and microglia rather than neurons.

Explain the mechanism:

What cellular route may carry virus into the CNS?

Name two classes of mediators proposed to cause neural dysfunction.

Why might symptoms be severe despite relatively modest structural lesions?

Slide 72 · Five causal links explain HIV-associated immunodeficiency

CD4 + coreceptor engagement initiates entry; Gp41 completes fusion.

Reverse transcription and integration enable lifelong genomic persistence.

Cell activation can convert latent infection into destructive replication.

Direct death, bystander injury, tissue damage, and poor renewal deplete T cells.

Myeloid, B-cell, and CNS effects expand disease beyond CD4⁺ lymphopenia.

Slide 73 · Primary reference

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

Chapter 6, “Diseases of the Immune System,” pp. 220–224.

Section: “Pathogenesis of HIV Infection and AIDS.”

Source-associated material: Figs. 6.38–6.40 and Table 6.14 (not reproduced).