• worldwide
• disproportionately affects developing countries and people of color
• highest rates in US: DC, Puerto Rico, NY, FL, MD
• declines in mortality over last several years
• increase in cases due to IVDA and heterosexual contact
• decrease in cases due to homosexual contact

• blood and body fluids
• sexual contacts
  • isolated from semen, vaginal secretions
• IVDA (share needles)
• blood and blood product transfusion
  • since serologic testing began in 1985, risk is VERY LOW

• viral load (advanced or early HIV infection)
• genital ulcer disease and other STD's
• antiretroviral therapy may decrease transmission

• genital ulcer disease, other STD's
• lack of circumcision (foreskin has many dendritic cells)
• traumatic sex/rectal sex
• cervical ectopy
• chemokine receptor phenotype (CCR5)

• w/o therapy, transmission 25-30% of time
• can occur in utero or blood contact at birth
• risk factors
  • premature rupture of membranes
  • chorioamnionitis
  • low maternal CD4/high HIV RNA
• can transmit via breast milk
• lower risk with cesarean
• reduction via AZT for baby and mother

• needlestick is a very low risk (0.3%)
• risk factors
  • parenteral>>mucosal (mouth, eye)>>non intact skin
  • inoculum: viral titer and volume of blood
  • needle type
    • hollow bore needles aka needle to draw blood>solid bore aka suture needle
    • large bore>small bore
• decrease risk with:
  • antiretroviral therapy initiated within 24 hours
  • glove use

• first thing to increase along with HIV increase is HIV specific CD8 lymphocytes
  • important part of cellular response to primary infection
  • stimulated by MHC I
• CD4 lymphocytes
  • function- facilitates activity of other CD4 cells, CD8 cells, NK cells, macrophages, B cells
• NK cells
• neutralizing (rise as HIV begins to level drop and level off) and non neutralizing Ab's
  • ADCC
• there are also proteins involved from the innate immune response

1. HIV trapped in lymph node by follicular dendritic cells
2. leads to infection of CD4 T cells (HALLMARK: CD4 cell depletion)
3. infects macrophages (act as possible vehicle into CNS)

• HIV mediated direct cytopathicity (single cell killing)
• HIV mediated syncytia formation with recruitment of non HIV infected individuals (innocent bystandard)
• virus specific immune responses
• super Ag effects
• apoptosis

• 2-4 weeks after infection the GALT can lose most of their CD4 cells (mainly memory CD4 cells)
• mucosal lining of GI carries disproportionately heavy viral load
• some CD4 cells become apoptotic while some appear to be killed by CD8 cells

• decrease number of CD4 cells
• loss of skin test reactivity/delayed type hypersensitivity
• decreased proliferation to mitogens, alloAg, recall Ag's
  • decrease in IL-2 production
• alteration in Th1/Th2 cytokine production and signaling pathways (more so towared Th2 profile)
• increase susceptibility to viral, fungal, and protozoal infections 

• polyclonal gammopathy
  • definition- nonspecific Ab response to multiple Ag's
• poor response to new immunogens (ex: pneumococcal vaccine)
• increased susceptibility to bacterial infections caused by encapsulated organisms

• HIV1 Ab's
  • screen via ELISA (serum or saliva) w/ false positve rate of 0.4% (very sensitive)
  • confirmatory via western bloot or IFA (false positive rate of 0.005%)
    • need specific HIV2 western blot
• HIV RNA/DNA

• occurs in 50-90% of seroconverters
• typically in 2-4 weeks after exposure
• infectious mononucleosis like illness
• may have viral meningitis
• early detection of HIV RNA
  • prior to Ab, the "window" period
• early treatment may alter natural history of HIV infection
• important period of transmission for new infections

• stage 1
  • CD4 greater than 500
  • clinical: no AIDS defining condition
• stage 2
  • CD4 between 200 and 499
  • clinical: no AIDS defining condition
• stage 3
  • CD4 less than 200
  • clinical: AIDS defining conditions

• Pneumocystitis jirovecii pneumonia
• candidiasis- esophagus, tracheobronchial
• cryptococcosis (extra pulmonary)
• histoplasmosis (extra pulmonary)
• coccidioidmycosis (extra pulmonary)

• MAC infection
• M tuberculosis
• M kansasii

• chronic mucocutaneous herpes simplex (oral, genital, perianal)
• CMV infection of major organs
• progressive multifocal leukoencephalopathy (PML, JC virus)

• cerebral toxoplasmosis
• intestinal parasites
  • cryptosporidiosis (protracted)
  • isoporiasis
  • extraintestinal strongyloidiasis

• recurrent bacterial pneumonia
• recurrent Salmonella bacteria

• risk related to degree of immunosuppression
• CD4 less than 200
  • Pneumocystitis jirovecii pneumonia
• CD4 less than 100
  • cryptococcal meningitis
  • CMV infection of major organs
  • MAC
  • cerberal toxoplasmosis

• Kaposi's sarcoma (HHV8 related)
• lymphoma (EBV related)
  • non Hodgkin's lymphoma
  • Burkitt's lymphoma
  • primary CNS lymphoma
• cervical cancer (HPV related)
• squamous cell carcinoma of rectum (HPV related)

• CNS shows HIV encephalopathy (progressive dementia)
• peripheral neuropathy
• spinal cord disease

• wasting syndrome
• thrombocytopenia
• renal disease
• cardiomyopathy

• median rate of progression if untreated is about 10 yrs
• determined by following cohorts of patients for which time of infection could be precisely determined
  • homosexual cohorts
  • blood or blood component recipients
• more rapid in neonates, elderly

HIV1 progression: role of genetic variants and tx

• related to HLA type
• chemokine receptor phenotype (CCR5 variant)
• less severe with HIV2

tx delay progression

• CD4 count
• symptoms
  • fever, chills, night sweats, weight loss
  • oral candidiasis
  • oral hairy leukoplakia (linear pattern on cheek, side of tongue)
• HIV RNA
  • baseline HIV RNA level is independent predictor of survival

• criteria (5-10% of HIV positive individuals)
  • preservation of CD34 cell numbers for 10-15 yrs after infection
  • undetectable HIV RNA
  • preservation of lymph node architecture
  • very strong CD8 T cell response

• combination therapy superior to monotherapy
  • more potent
  • delays resistance
• start with CD4 less than 350 or 400 or HIV RNA PCR less 50,000-100,000
• monitor effectiveness via
  • clinical evaluation
  • CD4 counts
  • plasma HIV RNA levels

• maximize suppression of viral replication
  • undetectable plasma HIV RNA level
• optimal preservation of immune function
  • maximize CD4 count
• delay emergence of resistance
• foster patient compliance
• minimize side effects, drug interactions
• preserve future tx options

• reverse transcriptase inhibitors
  • nucleoside/nucleotide analogs (NRTI's) aka chain terminating agents
  • non nucleoside RTI (NNRTI's)
    • bind to enzyme
    • cause confirmation change
    • make reverse transcriptase inactive
• protease inhibitors
• integrase inhibitors
• fusion/entry inhibitors
  • inhibitors of gp41 mediated fusion
  • chemockine coreceptor antagonists (ex: inh. of CCR5)

• high rate of viral replication
• high mutation frequency
• failure of reverse transcriptase to correct transcription errors
• point mutations lead to changes in shape, size, or charge of active site
• increasing incidence of transmission of resistance
• accumulation of mutations lead to increase resistance

• genotypic- characteristic codon mutations conferring resistance
• phenotypic- ability of virus to grow in vitro in presence of drug
• clinical- lack of clinical or virologic benefit in an individual patient (aka not getting better)

• adherence
  • multidrug therapy, high pill burden
  • inconvenient dosing schedules
• side effects
• complex drug interactions (P450)
• emergence of resistance

• lipodystrophy (fat redistribution)/lipoatrophy (loss of face fat)
  • due to inhibition of mitochondrial DNA polymerase
• immune reconstitution syndrome

• presentation of infection or worsening of the manifestations after initiation of antiretrovrial therapy
• due to increases in CD4 cell number or percentage and a fall in HIV RNA
• causes worsening of opportunisitc infections: TB, MAC, CMV, PCP

• cousneling, education
• barrier methods
• circumscision
• blood product screening
• therapy to prevent vertical transmission
  • antiretroviral therapy and cesarean
• post exposure therapy: needlestick, sexual contact, delivery
• in the future, pre exposure px in high risk individuals and vaccines

• foreskin full of dendritic cells
• persistent risk of transmission if never healed
• also decrease risk in genital ulcer if you get circumcised