Transmission of HIV infection

HIV-1 and HIV-2, the major and minor human AIDS viruses,are transmitted in ways that are typical for all retroviruses –“vertically” – that is from mother to infant, and “horizontally”through sexual intercourse and through infected blood. Thelymphocytes of a healthy carrier of HIV replicate, andeliminate, over one billion virions each day and the circulatingvirus “load” may exceed ten million virions per millilitre. Atthese times viraemia can be recognised by measuring the p24antigen of HIV in blood and quantifying viral DNA or RNA(see below). Transmission also depends on other factors,including the concentration of HIV secreted into body fluidssuch as semen, secondary infection of the genital tract, theefficiency of epithelial barriers, the presence or absence of cellswith receptors for HIV, and perhaps the immune competence ofthe exposed person. All infections with HIV appear to becomechronic and many are continuously productive of virus. Theultimate risk of spread to those repeatedly exposed is thereforehigh.The stage of infection is an important determinant ofinfectivity. High titres of virus are reached early in infection,though this phase is difficult to study because symptoms may bemild or absent and any anti-HIV response undetectable; it isnevertheless a time when an individual is likely to infectcontacts. When, much later, the cellular immune response toHIV begins to fail and AIDS supervenes the individual mayagain become highly infectious. In the interval between, theremay be periods when except through massive exposures – forexample blood donation – infected individuals are much lessinfectious. Nevertheless, in the absence of reliable markers ofinfectivity, all seropositive individuals must be seen aspotentially infectious, even those under successful treatment.Effective ways are constantly being sought to protect theircontacts and this has led to the development of the concept of“safe sex”. Ideally, this should inform sexual contact between allindividuals regardless of whether they are known to be infectedwith HIV.

Strategies for HIV vaccine development

• A good vaccine should induce neutralising antibody, helperT-cells and cytotoxic T-cells.

• Since antibodies bind to three dimensional structures,induction of neutralising antibody requires native envelope.Problem: Native envelope is trimeric.

• T-cells recognise 8–15 amino acid-long peptides bound toMajor Histocompatibility Complex (MHC) class I and IImolecules.Problem: Antigen needs to enter antigen presenting cells,usually dendritic cells, to be broken down to peptides.

• Peptides with novel adjuvants can generate good T-cellresponses.Problem: Different peptides bind to each MHC allele so alarge cocktail of different peptides may be needed.

• Adjuvants are needed to induce large responses.Problem: There are very few adjuvants available forunrestricted use in humans. Alum is mainly good for inductionof antibody responses.

• DNA immunisation can generate antibody, helper andcytotoxic responses and allows incorporation of adjuvantmolecules into the vaccine.Problem: So far DNA vaccination has not proved as effectivein man as in experimental animals.

• HIV is very variable and escape variants arise rapidly ininfected individuals. Prophylactic immunisation may tip thebalance in favour of the host and prevent escape. Some partsof the virus sequence are relatively invariant, these should betargeted if possible.

• In experimental animals immunisation with differentimmunogens appears promising. DNA vaccination followed byimmunisation with antigen in a recombinant viral vector seemsparticularly effective. This is now under trial in man.

History of the AIDS

The first recognised cases of the acquired immune deficiencysyndrome (AIDS) occurred in the summer of 1981 in America.Reports began to appear of Pneumocystis carinii pneumonia andKaposi’s sarcoma in young men, who it was subsequentlyrealised were both homosexual and immunocompromised. Eventhough the condition became known early on as AIDS, itscause and modes of transmission were not immediatelyobvious. The virus now known to cause AIDS in a proportionof those infected was discovered in 1983 and given variousnames. The internationally accepted term is now the humanimmunodeficiency virus (HIV). Subsequently a new variant hasbeen isolated in patients with West African connections –HIV-2.The definition of AIDS has changed over the years as aresult of an increasing appreciation of the wide spectrum ofclinical manifestations of infection with HIV. Currently, AIDSis defined as an illness characterised by one or more indicatordiseases. In the absence of another cause of immune deficiencyand without laboratory evidence of HIV infection (if thepatient has not been tested or the results are inconclusive),certain diseases when definitively diagnosed are indicative ofAIDS. Also, regardless of the presence of other causes ofimmune deficiency, if there is laboratory evidence of HIVinfection, other indicator diseases that require a definitive, orin some cases only a presumptive, diagnosis also constitute adiagnosis of AIDS.In 1993 the Centers for Disease Control (CDC) in the USAextended the definition of AIDS to include all persons who areseverely immunosuppressed (a CD4 count <200>

AIDS-defining conditions with laboratory evidence of HIV

• Diseases diagnosed definitively

• Recurrent/multiple bacterial infections in child <13>

• Coccidiomycosis – disseminated

• HIV encephalopathy• Histoplasmosis – disseminated

• Isosporiasis with diarrhoea persisting >1 month

• Kaposi’s sarcoma at any age

• Primary cerebral lymphoma at any age

• Non-Hodgkin’s lymphoma: diffuse, undifferentiated B cell type, or unknown phenotype

• Any disseminated mycobacterial disease other than M.tuberculosis

• Mycobacterial tuberculosis at any site

• Salmonella septicaemia: recurrent

• HIV wasting syndrome

• Recurrent pneumonia within 1 year

• Invasive cervical cancer

• Diseases diagnosed presumptively

• Candidiasis: oesophagus

• Cytomegalovirus retinitis with visual loss

• Kaposi’s sarcoma

• Mycobacterial disease (acid-fast bacilli; species not identified by culture): disseminated

• Pneumocystis carinii pneumonia

• Cerebral toxoplasmosis

Transmission of the HIV virus

HIV has been isolated from semen, cervical secretions,lymphocytes, cell-free plasma, cerebrospinal fluid, tears, saliva,urine, and breast milk. This does not mean, however, that thesefluids all transmit infection since the concentration of virus inthem varies considerably. Particularly infectious are semen,blood, and possibly cervical secretions. The commonest mode oftransmission of the virus throughout the world is by sexualintercourse. Whether this is anal or vaginal is unimportant.Other methods of transmission are through the receipt ofinfected blood or blood products, donated organs, and semen.Transmission also occurs through the sharing or reuse ofcontaminated needles by injecting drug users or for therapeuticprocedures, and from mother to child. Transmission frommother to child occurs in utero and also possibly at birth. Finally,the virus is transmitted through breast milk.The virus is not spread by casual or social contact. Healthcare workers can, however, be infected through needlestickinjuries, and skin and mucosal exposure to infected blood orbody fluids. Prospective studies in health care workers sufferingpercutaneous exposure to a known HIV seropositive patientindicate a transmission rate of 0.32%. As of December 1999there have been 96 reported cases of documentedseroconversion after occupational exposure in such workers.
The precautions and risks for such groups are covered indetail in chapter 15. Finally, there is no evidence that the virusis spread by mosquitoes, lice, bed bugs, in swimming pools, orby sharing cups, eating and cooking utensils, toilets, and airspace with an infected individual. Hence, HIV infection andAIDS are not contagious.

The HIV virus and the tests

Although it is clear that HIV is the underlying cause of AIDSand AIDS-related disease, its origin remains obscure. There isfirm serological evidence of infection on the east and westcoasts of the USA from the mid 1970s, and HIV infection incentral Africa may have antedated infection in North America.Phylogenetic analysis of the HIV-1 genome has suggested anorigin in chimpanzees while, in the case of HIV-2, similarity tothe simian immunodeficiency virus (SIV) genome may point toan origin in sooty mangabey monkeys. In both cases thebutchery and consumption of these “bush meats” has beenincriminated in transmissions to the human host. Like someother RNA viruses, HIV appears to have mutated and shifted itshost range and virulence, explaining how a new pathogenicretrovirus could arise in man. Its virulence may since have beenamplified as a result of travel, population dislocation andpromiscuous sexual contact, with rapid passage of the virus.
Retroviruses are so named because their genomes encode anunusual enzyme, reverse transcriptase, which allows DNA to betranscribed from RNA. Thus, HIV can make copies of its owngenome, as DNA, in host cells such as the human CD4 “helper”lymphocyte. The viral DNA becomes integrated in thelymphocyte genome, and this is the basis for chronic HIVinfection. Integration of the HIV genome into host cells is aformidable obstacle to any antiviral treatment that would notjust suppress but also eradicate the infection. Nevertheless,modern treatment with combinations of nucleoside analoguesand protease inhibitors has transformed the prognosis forcarriers of HIV, usually achieving a sustained fall in virusconcentration in blood and restoration of the main target cell(CD4 lymphocyte) to near normal levels.
By contrast, the inherent variability of the HIV genome andthe failure of the human host to produce neutralising antibodiesto the virus, as well as technical difficulties and concerns aboutsafety, have continued to frustrate attempts to make an effectivevaccine. This must not, however, allow efforts to develop andevaluate candidate vaccines to slacken. A particular concern isthat a useful candidate vaccine (probably a recombinantenvelope vaccine developed in North America or Europe againstthe locally prevalent HIV-1 B subtype) would be ineffective inthose parts of the world where other subtypes predominate.
WHO estimates that in the year 2000 there are 36 millioncarriers of HIV worldwide, and only a small fraction of themhave access to suppressive treatment. Both their contacts, theirdependants and possibly they themselves would have their lifeprospects transformed by an effective, or even partially effective,vaccine, and successful application of antiviral treatment indeveloped countries should in no way be allowed to deflectattention from the necessity of developing and delivering aneffective vaccine and of promoting “safe sex” behaviour.

HIV and related viruses

HIV was discovered by Barré-Sinoussi, Montagnier, andcolleagues at the Institut Pasteur, Paris, in 1983 and given thename lymphadenopathy associated virus (LAV). In 1984Popovic, Gallo, and co-workers described the development ofcell lines permanently and productively infected with the virus.In line with two previously described retroviruses, HTLV-I andHTLV-II, they designated this virus HTLV-III. Other virusisolates from patients with AIDS and AIDS-related disease inAmerica, Europe and Central Africa have proved to be all thesame virus, now referred to as HIV-1. Eight subtypes of HIV-1,alphabetically designated, have so far been described.Around 1985 another human retrovirus, different from HIV-1, was recognised in patients from West Africa. This virus,referred to by the Paris investigators as LAV-2 and morerecently as HIV-2, is also associated with human AIDS andAIDS-related disease. It is closely related to the simianretrovirus, SIV, carried by healthy African green monkeys, andthe cause of an AIDS-like disease in captive rhesus monkeys.Though potentially important worldwide, HIV-2 infectionsremain uncommon outside West Africa and they have proved farless virulent than HIV-1 infections.

Diagnosis of Acute Abdominal Pain

Peritonitis

HISTORY - Pain severe and generalized; prostration; fever/chills; movement worsens pain.

PHYSICAL EXAM - Fever; generalized abdominal tenderness with guarding, rigidity, and rebound tenderness; decreased bowel sounds; patient lies still; hypotension, tachycardia, pallor, and sweating may be present.
Perforation of viscus

HISTORY - Pain severe and generalized.

PHYSICAL EXAM - Signs of peritonitis
Bowel infarction

HISTORY - Patient is usually older than 50 years of age (unless arterial embolus is the causative factor). Pain is often diffuse and may not reach maximal intensity for hours; bloody diarrhea occasionally.

PHYSICAL EXAM - Hypotension, tachycardia, pallor, and sweating may be present; signs of peritonitis; abdominal distension.
Bowel obstruction

HISTORY - Nausea, vomiting, often a preceding history of constipation, abdominal distension; pain may wax and wane; history of abdominal surgery.

PHYSICAL EXAM - Abdominal distension with generalized tympanitic percussion; high pitched rushing bowel sounds early, decreased later; patient tosses and turns.
Rupture of an abdominal aortic aneurysm

HISTORY - Acute abdominal, low back, or flank pain.

PHYSICAL EXAM - Pulsatile abdominal mass; hypotension, tachycardia, and asymmetrical pulses may be present.
Myocardial infarction

HISTORY - Severe, epigastric discomfort most common in persons over age 50, women, and diabetics; occasional nausea and vomiting

PHYSICAL EXAM - Diphoresis; no abdominal tenderness
Appendicitis

HISTORY - Initially pain is epigastric/periumbilical. Often progresses to right lower quadrant. Onset gradual, progressing over hours.

PHYSICAL EXAM - Low-grade fever (less than 101°F); right lower quadrant tenderness on abdominal or rectal exam; bowel sounds variable; peritonitis if perforation occurs. Obturator/psoas tests are often positive. Rebound tenderness referred to right lower quadrant.
Hepatitis

HISTORY - Malaise, myalgia, nausea, and right upper quadrant pain.

PHYSICAL EXAM - Hepatic tenderness and enlargement. Jaundice may be present.
Diverticulitis

HISTORY - Pain in lower left quadrant; constipation; nausea, often vomiting; course lasts several days. 25% of patients may have minor rectal bleeding.

PHYSICAL EXAM - Fever; lower left quadrant tenderness and fullness or mass; occasional rectal mass and tenderness; decreased bowel sounds. Localized signs of peritonitis may be present.
Cholecystitis

HISTORY - Colicky pain in epigastrium or right upper quadrant, occasionally radiating to right scapula; colicky with nausea, vomiting, fever; sometimes chills, jaundice, dark urine, light-colored stools (obstruction of common duct); may be recurrent.

PHYSICAL EXAM - Fever; right upper quadrant tenderness with guarding, occasional rebound; decreased bowel sounds.
Pancreatitis

HISTORY - Upper abdominal pain, occasionally radiating to back; mild to severe; associated with nausea/ vomiting; history of alcoholism or gallstones; often recurrent; pain may be eased by sitting up or leaning forward.

PHYSICAL EXAM - Periumbilical tenderness; occasionally associated with hypotension, tachycardia, pallor, and sweating; bowel sounds decreased.
Salpingitis pelvic inflammatory disease (females)

HISTORY - Pain initially in lower quadrants but may be generalized; usually severe; fever/chills occasionally; dyspareunia; occasional vaginal discharge.

PHYSICAL EXAM - Fever; tenderness with guarding/rebound in lower quadrants; pain on lateral motion of cervix; adnexal tenderness; purulent discharge from cervix.
Ruptured ectopic pregnancy (females)

HISTORY - Last menstrual period more than 6 weeks previous; pain in one lower quadrant; acute onset and severe

PHYSICAL EXAM - Adnexal tenderness and mass; postural hypotension and tachycardia may be present.
Ureteral stone

HISTORY - May note a history of previous “kidney stone”; pain may begin in flank and radiate to groin; painful urination and blood in urine are frequently noted.

PHYSICAL EXAM - Often unremarkable; flank tenderness may be noted as well as decreased bowel sounds. Fever is noted if urinary tract infection occurs.
Reflux esophagitis

HISTORY - Burning, epigastric or substernal pain radiating up to jaws; worse when lying flat or bending over, particularly soon after meals; relieved by antacids or sitting upright.

PHYSICAL EXAM - Patient often obese; normal abdominal exam.
Peptic ulcer or (nonulcerative) dyspepsia

HISTORY - Burning or gnawing, localized episodic or recurrent epigastric pain appearing 1–4 hours after meals; may be made worse by alcohol, aspirin, steroids, or other anti-inflammatory medications; relieved by antacids or food.

PHYSICAL EXAM - Deep epigastric tenderness.
Ulcerative colitis

HISTORY - Rectal urgency; recurrent defecation of small amounts of semiformed stool; pain worsens just before bowel movements; blood in stools

PHYSICAL EXAM - Low-grade fever; tenderness over colon; rectal tenderness and commonly blood in stools; weight loss may be present.
Regional enteritis

HISTORY - Pain in right lower quadrant or periumbilical; usually in young persons; insidious onset; may be relieved by defecation; stools are often soft and unformed.

PHYSICAL EXAM - Low-grade fever; periumbilical or right quadrant tenderness or mass; weight loss may be present
Irritable bowel

HISTORY - Recurrent abdominal discomfort and/or change in bowel habits aggravated by anxiety; diarrhea often alternates with constipation; diarrhea and constipation may also be the predominant symptom.

PHYSICAL EXAM - No fever; minimal abdominal tenderness over the course of the large bowel or normal abdominal exam; rectal examination is normal and feces contain no blood.

AIDS-defining conditions without laboratory evidence of HIV

• Diseases diagnosed definitively

• Candidiasis: oesophagus, trachea, bronchi or lungs

• Cryptococcosis: extrapulmonary

• Cryptosporidiosis with diarrhoea persisting >1 month

• Cytomegalovirus disease other than in liver, spleen, nodes

• Herpes simplex virus (HSV) infection

• mucocutaneous ulceration lasting >1 month

• pulmonary, oesophageal involvement

• Kaposi’s sarcoma in patient <60>

• Primary cerebral lymphoma in patient <60>

• Lymphoid interstitial pneumonia in child <13>

• Mycobacterium avium: disseminated

• Mycobacterium kansasii: disseminated

• Pneumocystis carinii pneumonia

• Progressive multifocal leukoencephalopathy

• Cerebral toxoplasmosis